Heterocyclic compounds having cholesterol 24-hydroxylase activity

ABSTRACT

An object of the present invention is to provide a compound having a superior CH24H inhibitory action, which is useful as an agent for the prophylaxis or treatment of epilepsy, neurodegenerative disease and the like. The present invention relates to a compound represented by the formula: 
     
       
         
         
             
             
         
       
     
     wherein each symbol is as defined in the specification, or a salt thereof.

TECHNICAL FIELD

The present invention relates to a heterocyclic compound having acholesterol 24-hydroxylase (in the present specification, sometimes tobe abbreviated as “CH24H”) inhibitory action, a pharmaceuticalcomposition comprising same, and the like.

BACKGROUND OF THE INVENTION

Alzheimer's disease is a progressive neurodegenerative diseasecharacterized by the deposition of amyloid β protein (Aβ), accumulationof phosphorylated tau in a nerve cell (neurofibrillary tangle), andnerve cell death. In recent years, the number of patients withAlzheimer's disease is increasing because of aging, but an effectivetreatment method has not been developed as yet. The therapeutic drugsfor Alzheimer's disease which are currently used in the medical practiceare mainly acetylcholinesterase (AchE) inhibitors. While AchE inhibitorsis confirmed to provide a certain level of usefulness, since they areused with the aim of supplementing decreased acetylcholine, thetreatment with AchE inhibitor is merely a symptomatic therapy. Thus, theprompt development of a basic remedy and prophylactic drug has beenstrongly desired.

It has been clarified that the presence of allele ε4 of apolipoprotein E(ApoE) controlling the cholesterol metabolism is a strong risk factor ofAlzheimer's disease [non-patent document 1: Science, vol. 261, 921-923,1993]. After this finding, the correlation between plural genepolymorphisms playing a role in the expression of protein controllingthe cholesterol metabolism and the onset frequency of Alzheimer'sdisease has been shown, suggesting the correlation between thecholesterol metabolism and Alzheimer's disease [non-patent document 2:Neurobiol. Aging, vol. 24, 421-426, 2003, non-patent document 3: Mol.Psychiatry, vol. 8, 635-638, 2003]. Moreover, it has been reported thatCyp46 (same as “cholesterol 24-hydroxylase (CH24H)”), which ischolesterol oxidase specifically expressed in the brain, is a riskfactor of Alzheimer's disease [non-patent document 4: Neurosci. Lett.,vol. 328, pages 9-12, 2002]. Furthermore, it has also been reported thatCyp46 (CH24H) is expressed in periphery of deposited amyloid inAlzheimer's disease patients [non-patent document 5: J. Biol. Chem.,vol. 279, pages 34674-34681, 2004], 24S-hydroxycholesterol (24-HC),which is a metabolite thereof, increases in the brain spinal cord fluid(CSF) of Alzheimer's disease patients [non-patent document 6: Neurosci.Lett., vol. 324, pages 83-85, 2002, non-patent document 7: Neurosci.Lett., vol. 397, pages 83-87, 2006], 24-HC induces cell death of SH-SY5Ycell, which is a human neuroblast line [non-patent document 8: BrainRes., vol. 818, pages 171-175, 1999], and rats in which 24-HC wasinjected into the lateral cerebral ventricle showed impaired short-termmemory, which is commonly observed in Alzheimer's disease, suggestingthat hippocampal neurons were damaged by 24-HC [non-patent document 9:Neuroscience, vol. 164, pages 398-403, 2009]. These findings suggestthat Cyp46 (CH24H) is deeply involved in the pathology of Alzheimer'sdisease. Therefore, a compound that inhibits the Cyp46 (CH24H) activity(i.e., Cyp46 (CH24H) inhibitor) suppresses neuronal cell death, increasein Aβ, intracerebral inflammation and the like observed in Alzheimer'sdisease, by decreasing intracerebral 24-HC, and is promising as atherapeutic or prophylactic drug showing not only an improvement ofsymptoms but also a suppression of progression. Moreover, it has beenreported that an AchE inhibitor clinically used as a therapeutic drugfor Alzheimer's disease shows an improvement effect on memory disordersinduced by Aβ in mouse [non-patent document 10: British Journal ofPharmacology, vol. 149, pages 998-1012, 2006]. Thus, a Cyp46 (CH24H)inhibitor showing an improvement effect for memory disorders in Aβoverexpression animal model (APP transgenic mouse, APP/PS1 doubletransgenic mouse, etc.) is promising as a therapeutic drug forAlzheimer's disease.

As a concept of the preclinical stage of Alzheimer's disease, a mildcognitive impairment has been proposed, and about half of those havingthis disorder is said to progress into the Alzheimer's disease in thefuture. In recent years, it has been reported that 24-HC increases notonly in patients with Alzheimer's disease but also in CSF of patientswith mild cognitive impairment [non-patent document 7: Neurosci. Lett.,vol. 397, pages 83-87, 2006]. This finding suggests that Cyp46 (CH24H)is involved in the pathology of mild cognitive impairment, andtherefore, a Cyp46 (CH24H) inhibitor is promising as a new therapeuticdrug for Alzheimer's disease or a prophylactic drug for the progressioninto the Alzheimer's disease.

In recent years, moreover, it has been reported that 24-HC in the bloodincreases before expression of the symptom in an autoimmuneencephalomyelitis model, which is an animal model of multiple sclerosiswhich is one of the demyelination diseases in the central nervous system[non-patent document 11: J. Neurosci. Res., vol. 85, pages 1499-1505,2007]. Multiple sclerosis is often developed in younger people of about30 years old, and scarcely developed in the elderly of 60 years orolder. It has also been reported that 24-HC in the blood increases inmultiple sclerosis patients aged from 21 to 50 [non-patent document 12:Neurosci. Lett., vol. 331, pages 163-166, 2002]. These findings suggestthat Cyp46 (CH24H) is involved in the pathology of multiple sclerosis,and therefore, a Cyp46 (CH24H) inhibitor is promising as a newtherapeutic or prophylactic drug for multiple sclerosis.

Traumatic brain injury (also referred to as TBI in the presentspecification) is a condition having an extremely harmful influence onthe personal health, for which no effective cure has been established.In the repair process following tissue damage by TBI, reconstruction ofneuronal cell membrane and distribution of intracerebral cholesterolalong with the growth of glial cell are suggested to be activated[non-patent document 13: Proc. Natl. Acad. Sci. USA, vol. 102, pages8333-8338, 2005]. In a rat TBI model, an enhanced expression of Cyp46(CH24H) after trauma has been reported [non-patent document 14: J.Neurotrauma, vol. 25, pages 1087-1098, 2008]. Moreover, it has also beenreported that 24-HC is injurious to neuronal cells [non-patent document8: Brain Res., vol. 818, pages 171-175, 1999]. Therefore, a Cyp46(CH24H) inhibitor is promising as a new therapeutic or prophylactic drugfor TBI.

As a pathological significance of 24-HC in neurodegenerative diseases,an inflammatory gene expression-enhancing action in neuronal cells hasbeen reported [non-patent document 15: NeuroReport, vol. 16, pages909-913, 2005]. In addition, it is suggested that an intracerebralinflammation reaction accompanied by activation of glial cell is apathological change characteristic of neurodegenerative diseases[non-patent document 16: Glia, vol. 50, pages 427-434, 2005]. In recentyears, an effectiveness of therapy by suppression of intracerebralinflammation has also been reported for neurodegenerative diseases suchas Huntington's disease, Parkinson's disease and amyotrophic lateralsclerosis and the like [non-patent document 17: Mol. Neurodegeneration,vol. 4, pages 47-59, 2009]. Therefore, suppression of intracerebralinflammation via decreasing 24-HC by the inhibition of Cyp46 (CH24H) ispromising as a new therapeutic or prophylactic drug forneurodegenerative diseases such as Huntington's disease, Parkinson'sdisease, cerebral infarction, glaucoma, amyotrophic lateral sclerosisand the like.

Glaucoma is the main cause of blindness, and is considered to be aserious social problem. However, there is no effective cure of a normalintraocular pressure type-visual field constriction, which is the majorsymptom of the disease. In recent years, it has been reported that genepolymorphisms of Cyp46 (CH24H) associated with high value of 24-HC inblood is related to the risk of the onset of glaucoma [non-patentdocument 18: Invest. Ophthalmol. Vis. Sci., vol. 50, pages 5712-5717,2009]. Thus, a Cyp46 (CH24H) inhibitor is promising as a therapeutic orprophylactic drug for glaucoma.

Spasm is a disorder that convulsively occurs with abnormal electricalexcitation of neuronal cell in the brain. Spasm is one of thecharacteristic clinical findings of Alzheimer's disease [Non-PatentDocument 19: Epilepsia, vol. 47, pages 867-872, 2006], and therelationship between epilepsy and onset of Alzheimer's disease has beenindicated [Non-Patent Document 20: Epilepsia, vol. 52, Supplement 1,pages 39-46, 2011]. It has been reported that spasm occurs with highfrequency in APP/PS1 double transgenic mouse which is one of theAlzheimer's disease models due to AR overexpression [non-patent document21: J. Neurosci., vol. 29, pages 3453-3462, 2012]. Furthermore, sincehippocampus astrocytes induce the expression of Cyp46 (CH24H) in akainic acid lesion rat model, which is one of the epilepsy models, therelationship between this enzyme and pathology of epilepsy has beenindicated [Non-Patent Document 22: J. Neurol., vol. 65, pages 652-663,2006]. It has been reported that a therapeutic drug for spasm,carbamazepine, shows an improving effect on short-term memory in Y-mazetest in an epileptic spasm mouse model [Non-Patent Document 23: J.Neurol. Neurosurg. Psychiatry, vol. 48, pages 459-468, 1985]. Therefore,a CH24H inhibitor, which shows an improving effect on short-term memoryin a model animal showing a spasm symptom, is promising as a noveltherapeutic drug or prophylaxis drug for spasm, epilepsy, and the like.

Since schizophrenia shows a variety of psychological symptoms such ashallucination, delusion, excitation, manic-depressive state and thelike, therapeutic drugs therefor have been developed with variousapproaches. In recent years, it has been pointed out that changes in thecholesterol metabolism are involved in the abnormality of neuralactivity seen in schizophrenia [non-patent document 24: J. PsychiatryNeurosci., vol. 36, pages 47-55, 2011]. Since cytotoxic factors such asoxidative stress also contribute to the pathology of schizophrenia,neuronal cell toxicity of 24-HC may aggravate the symptoms [non-patentdocument 25: Psychoneuroendocrinology, vol. 28, pages 83-96, 2003].Therefore, a Cyp46 (CH24H) inhibitor that inhibits metabolizingcholesterol to 24-HC in the brain is promising as a therapeutic orprophylactic drug for schizophrenia.

Examples of the compound having a structure similar to the compounddescribed in the present specification include the following compounds.

Patent Document 1 discloses the following compound as an agent for thetreatment of HIV, AIDS and the like.

wherein

Ring A is

R¹ is a hydrogen atom, C₁₋₄ alkyl or the like;R² is a hydrogen atom;R⁴-R⁷ are independently a hydrogen atom, a halogen atom or the like;

X is N or CH;

Y is a 5- to 7-membered monocyclic aromatic heterocycle or the like;Z is aryl or an aromatic heterocyclic group; andR⁹-R¹⁶ are independently a hydrogen atom, C₁₋₆ alkyl or the like.

Patent Document 2 discloses the following compound having a CH24Hinhibitory action as an agent for the treatment of neurodegenerativedisease (e.g., Alzheimer's disease, mild cognitive disorder, multiplesclerosis and the like).

whereinRing A^(a) is an optionally substituted ring;

R^(1a) is

(1) a group represented by the formula: —X^(1a)—R^(6a)

-   -   wherein X^(1a) is a C₁₋₆ alkylene group, a C₂₋₆ alkenylene group        or a C₃₋₆ cycloalkylene group, and R^(6a) is an optionally        substituted C₆₋₁₄ aryl group, an optionally substituted C₆₋₁₄        aryloxy group or an optionally substituted heterocyclic group,        (2) an optionally substituted C₆₋₁₄ aryl group,        (3) an optionally substituted C₆₋₁₄ aryloxy group, or        (4) an optionally substituted heterocyclic group;        R^(2a) is a hydrogen atom, an optionally substituted C₁₋₆ alkyl        group, an optionally substituted C₃₋₆ cycloalkyl group or an        optionally substituted hydroxy group,        R^(3a) is an optionally substituted C₁₋₆ alkyl group, an        optionally substituted C₃₋₆ cycloalkyl group or an optionally        substituted hydroxy group, or        R^(2a) and R^(3a) in combination optionally form an oxo group, a        C₁₋₃ alkylidene group or an optionally substituted ring; and        R^(4a) and R^(5a) are the same or different and each is a        hydrogen atom, a halogen atom, an optionally substituted C₁₋₆        alkyl group, an optionally substituted C₃₋₆ cycloalkyl group or        an optionally substituted hydroxy group, or        R^(4a) and R^(5a) in combination optionally form an oxo group, a        C₁₋₃ alkylidene group or an optionally substituted ring.

Patent Document 3 discloses the following compound having acalcium-sensing receptor (CaSR) antagonistic action as an agent for thetreatment of bone disease (e.g., osteoporosis, bone fracture and thelike).

whereinRing A^(a) is an optionally substituted ring;

R^(1a) is

(1) a group represented by the formula: —X^(1a)—R^(6a)

-   -   wherein X^(1a) is a C₁₋₆ alkylene group, a C₂₋₆ alkenylene group        or a C₃₋₆ cycloalkylene group, and R^(6a) is an optionally        substituted C₃₋₆ cycloalkyl group, an optionally substituted        C₃₋₆ cycloalkyloxy group, an optionally substituted C₆₋₁₄ aryl        group, an optionally substituted C₆₋₁₄ aryloxy group, an        optionally substituted C₇₋₁₄ aralkyloxy group, an optionally        substituted heterocyclic group, an optionally substituted        heterocyclyloxy group or optionally substituted amino group,        (2) an optionally substituted C₃₋₆ cycloalkyl group,        (3) an optionally substituted C₃₋₆ cycloalkyloxy group,        (4) an optionally substituted C₆₋₁₄ aryl group,        (5) an optionally substituted C₆₋₁₄ aryloxy group,        (6) an optionally substituted C₇₋₁₄ aralkyloxy group,        (7) an optionally substituted heterocyclic group,        (8) an optionally substituted heterocyclyloxy group, or        (9) an optionally substituted amino group;        R^(2a) is a hydrogen atom, an optionally substituted C₁₋₆ alkyl        group, an optionally substituted C₃₋₆ cycloalkyl group or an        optionally substituted hydroxy group,        R³ is an optionally substituted C₁₋₆ alkyl group, an optionally        substituted C₃₋₆ cycloalkyl group or an optionally substituted        hydroxy group, or        R^(2a) and R^(3a) in combination optionally form a C₁₋₃        alkylidene group or an optionally substituted ring; and        R^(4a) and R^(5a) are the same or different and each is a        hydrogen atom, a halogen atom, an optionally substituted C₁₋₆        alkyl group, an optionally substituted C₃₋₆ cycloalkyl group or        an optionally substituted hydroxy group, or        R^(4a) and R^(5a) in combination optionally form an oxo group, a        C₁₋₃ alkylidene group or an optionally substituted ring.

DOCUMENT LIST Patent Document

-   Patent Document 1: WO 2007/127635-   Patent Document 2: WO 2010/110400-   Patent Document 3: JP 2010-248183

Non-Patent Document

-   Non-Patent Document 1: Science, vol. 261, pages 921-923, 1993-   Non-Patent Document 2: Neurobiology of Aging (Neurobiol. Aging),    vol. 24, pages 421-426, 2003-   Non-Patent Document 3: Molecular Psychiatry (Mol. Psychiatry), vol.    8, pages 635-638, 2003-   Non-Patent Document 4: Neuroscience Letters (Neurosci. Lett.), vol.    328, pages 9-12, 2002-   Non-Patent Document 5: Journal of the Biological Chemistry (J. Biol.    Chem.), vol. 279, pages 34674-34681, 2004-   Non-Patent Document 6: Neuroscience Letters (Neurosci. Lett.), vol.    324, pages 83-85, 2002-   Non-Patent Document 7: Neuroscience Letters (Neurosci. Lett.), vol.    397, pages 83-87, 2006-   Non-Patent Document 8: Brain Research (Brain Res.), vol. 818, pages    171-175, 1999-   Non-Patent Document 9: Neuroscience, vol. 164, pages 398-403, 2009-   Non-Patent Document 10: British Journal of Pharmacology, vol. 149,    pages 998-1012, 2006-   Non-Patent Document 11: Journal of Neuroscience Research (J.    Neurosci. Res.), vol. 85, pages 1499-1505, 2007-   Non-Patent Document 12: Neuroscience Letters (Neurosci. Lett.), vol.    331, pages 163-166, 2002-   Non-Patent Document 13: Proceedings of the National Academy of    Sciences USA (Proc. Natl. Acad. Sci. USA), vol. 102, pages    8333-8338, 2005-   Non-Patent Document 14: Journal of Neurotrauma (J. Neurotrauma),    vol. 25, pages 1087-1098, 2008-   Non-Patent Document 15: NeuroReport, vol. 16, pages 909-913, 2005-   Non-Patent Document 16: Glia, vol. 50, pages 427-434, 2005-   Non-Patent Document 17: Molecular Neurodegeneration (Mol.    Neurodegeneration), vol. 4, pages 47-59, 2009-   Non-Patent Document 18: Investigative Ophthalmology & Visual Science    (Invest. Opthalmol. Vis. Sci.), vol. 50, pages 5712-5717, 2009-   Non-Patent Document 19: Epilepsia, vol. 47, pages 867-872, 2006-   Non-Patent Document 20: Epilepsia, vol. 52, Supplement 1, pages    39-46, 2011-   Non-Patent Document 21: Journal of Neuroscience (J. Neurosci.), vol.    29, pages 3453-3462, 2012-   Non-Patent Document 22: Journal of Neurology (J. Neurol.), vol. 65,    pages 652-663, 2006-   Non-Patent Document 23: Journal of Neurology Neurosurgery Psychiatry    (J. Neurol. Neurosurg. Psychiatry), vol. 48, pages 459-468, 1985-   Non-Patent Document 24: Journal of Psychiatry Neuroscience (J.    Psychiatry Neurosci.), vol. 36, pages 47-55, 2011-   Non-Patent Document 25: Psychoneuroendocrinology, vol. 28, pages    83-96, 2003

SUMMARY OF THE INVENTION Problems to be Solved by the Invention

An object of the present invention is to provide a compound having asuperior CH24H inhibitory action, which is useful as an agent for theprophylaxis or treatment of epilepsy, neurodegenerative disease (e.g.,Alzheimer's disease, mild cognitive disorder, Huntington's disease,Parkinson's disease, multiple sclerosis, amyotrophic lateral sclerosis,traumatic brain injury, cerebral infarction, glaucoma and the like),schizophrenia and the like.

Means of Solving the Problem

The present inventors have conducted intensive studies in an attempt tosolve the above-mentioned problem and found that a compound (I)represented by the following formula has a superior CH24H inhibitoryaction, which resulted in the completion of the present invention.

Accordingly, the present invention provides the following.

[1] A compound represented by the formula (I):

wherein

X¹ is a carbon atom or a nitrogen atom;

Ring A is

each of which is optionally further substituted and optionally bridged;

R¹ is an optionally substituted C₁₋₆ alkyl group, an optionallysubstituted hydroxy group, an optionally substituted amino group, anoptionally substituted carbocyclic group, or an optionally substitutedheterocyclic group, or R¹ is optionally bonded to the atom on Ring A toform, together with Ring A, a spiro ring or a fused ring, each of whichis substituted by an oxo group and optionally further substituted;

R² is an optionally substituted C₆₋₁₄ aryl group, or an optionallysubstituted aromatic heterocyclic group; and

R³ is a hydrogen atom or a substituent when X¹ is a carbon atom, orabsent when X¹ is a nitrogen atom, (hereinafter to be referred to ascompound (I)) (tert-butyl4-(4-phenylpyrimidin-5-yl)piperazine-1-carboxylate is excluded) or asalt thereof.

[2] The compound or salt of [1], wherein R¹ is an optionally substitutedC₁₋₆ alkyl group, an optionally substituted C₁₋₆ alkoxy group, anoptionally substituted amino group, an optionally substituted C₃₋₈cycloalkyl group, an optionally substituted C₆₋₁₄ aryl group, or anoptionally substituted non-aromatic heterocyclic group (tert-butyl4-(4-phenylpyrimidin-5-yl)piperazine-1-carboxylate is excluded).[A] The compound or salt of [1], wherein

R¹ is

(1) a C₁₋₆ alkyl group optionally substituted by 1 to 3 substituentsselected from

-   -   (a) a cyano group,    -   (b) a C₆₋₁₄ aryl group optionally substituted by 1 to 3 C₁₋₆        alkoxy groups,    -   (c) a C₆₋₁₄ aryloxy group,    -   (d) a C₃₋₈ cycloalkyl group,    -   (e) a 5- or 6-membered monocyclic aromatic heterocyclic group,    -   (f) a 8- to 12-membered fused aromatic heterocyclic group, and    -   (g) a 3- to 8-membered monocyclic non-aromatic heterocyclic        group optionally substituted by 1 to 3 oxo groups,        (2) a C₁₋₆ alkoxy group optionally substituted by 1 to 3 C₆₋₁₄        aryl groups,        (3) an amino group optionally mono- or di-substituted by        substituent(s) selected from    -   (a) a C₁₋₆ alkyl group optionally substituted by 1 to 3        substituents selected from        -   (i) a halogen atom,        -   (ii) a cyano group,        -   (iii) a C₃₋₈ cycloalkyl group,        -   (iv) a C₆₋₁₄ aryl group optionally substituted by 1 to 3            substituents selected from a halogen atom and a C₁₋₆ alkoxy            group,        -   (v) a 5- or 6-membered monocyclic aromatic heterocyclic            group, and        -   (vi) a 3- to 8-membered monocyclic non-aromatic heterocyclic            group optionally substituted by 1 to 3 C₁₋₆ alkyl groups,    -   (b) a C₃₋₈ cycloalkyl group optionally substituted by 1 to 3        halogen atoms,    -   (c) a C₆₋₁₄ aryl group, and    -   (d) a 3- to 8-membered monocyclic non-aromatic heterocyclic        group optionally substituted by 1 to 3 C₁₋₆ alkyl groups,        (4) a C₃₋₈ cycloalkyl group optionally substituted by 1 to 3        C₆₋₁₄ aryl groups,        (5) a C₆₋₁₄ aryl group, or        (6) a 3- to 12-membered non-aromatic heterocyclic group        optionally substituted by 1 to 5 substituents selected from    -   (a) a halogen atom,    -   (b) a cyano group,    -   (c) a hydroxy group,    -   (d) an oxo group,    -   (e) a carbamoyl group optionally mono- or di-substituted by C₁₋₆        alkyl group(s),    -   (f) a C₁₋₆ alkyl group optionally substituted by 1 to 3        substituents selected from        -   (i) a hydroxy group, and        -   (ii) a C₁₋₆ alkoxy group,    -   (g) a C₁₋₆ alkoxy group optionally substituted by 1 to 3 halogen        atoms,    -   (h) a C₁₋₆ alkoxy-carbonyl group, and    -   (i) a C₆₋₁₄ aryl group optionally substituted by 1 to 3 halogen        atoms, or        R¹ is bonded to the atom on Ring A to form, together with Ring        A, a spiro ring substituted by oxo and optionally further        substituted by 1 to 3 C₁₋₆ alkyl groups;

R² is

(1) a C₆₋₁₄ aryl group optionally substituted by 1 to 3 substituentsselected from

-   -   (a) a halogen atom, and    -   (b) a C₁₋₆ alkyl group optionally substituted by 1 to 3 halogen        atoms, or        (2) a 5- to 12-membered aromatic heterocyclic group optionally        substituted by 1 to 3 substituents selected from    -   (a) a halogen atom,    -   (b) a cyano group,    -   (c) a C₁₋₆ alkyl group optionally substituted by 1 to 3 halogen        atoms, and    -   (d) a C₃₋₈ cycloalkyl group;

X¹ is a carbon atom or a nitrogen atom;

R³ is

(1) a hydrogen atom, or(2) a halogen atom; and

Ring A is

each of which is optionally bridged and optionally further substitutedby 1 to 5 substituents selected from

(a) a halogen atom,

(b) a C₁₋₆ alkyl group, and

(c) an oxo group,

(tert-butyl 4-(4-phenylpyrimidin-5-yl)piperazine-1-carboxylate isexcluded).[B] The compound or salt of [1] or [A], wherein R¹ is(1) a C₁₋₆ alkyl group optionally substituted by 1 to 3 substituentsselected from

-   -   (a) a cyano group,    -   (b) a C₆₋₁₄ aryl group optionally substituted by 1 to 3 C₁₋₆        alkoxy groups,    -   (c) a C₆₋₁₄ aryloxy group,    -   (d) a C₃₋₈ cycloalkyl group,    -   (e) a 5- or 6-membered monocyclic aromatic heterocyclic group,    -   (f) a 8- to 12-membered fused aromatic heterocyclic group, and    -   (g) a 3- to 8-membered monocyclic non-aromatic heterocyclic        group optionally substituted by 1 to 3 oxo groups,        (2) a C₁₋₃ alkoxy group optionally substituted by 1 to 3 C₆₋₁₄        aryl groups,        (3) an amino group optionally mono- or di-substituted by        substituent(s) selected from    -   (a) a C₁₋₆ alkyl group optionally substituted by 1 to 3        substituents selected from        -   (i) a halogen atom,        -   (ii) a cyano group,        -   (iii) a C₃₋₈ cycloalkyl group,        -   (iv) a C₆₋₁₄ aryl group optionally substituted by 1 to 3            substituents selected from a halogen atom and a C₁₋₆ alkoxy            group,        -   (v) a 5- or 6-membered monocyclic aromatic heterocyclic            group, and        -   (vi) a 3- to 8-membered monocyclic non-aromatic heterocyclic            group optionally substituted by 1 to 3 C₁₋₆ alkyl groups,    -   (b) a C₃₋₈ cycloalkyl group optionally substituted by 1 to 3        halogen atoms,    -   (c) a C₆₋₁₄ aryl group, and    -   (d) a 3- to 8-membered monocyclic non-aromatic heterocyclic        group optionally substituted by 1 to 3 C₁₋₆ alkyl groups,        (4) a C₃₋₈ cycloalkyl group optionally substituted by 1 to 3        C₆₋₁₄ aryl groups,        (5) a C₆₋₁₄ aryl group, or        (6) a 3- to 12-membered non-aromatic heterocyclic group        optionally substituted by 1 to 5 substituents selected from    -   (a) a halogen atom,    -   (b) a cyano group,    -   (c) a hydroxy group,    -   (d) an oxo group,    -   (e) a carbamoyl group optionally mono- or di-substituted by C₁₋₆        alkyl group(s),    -   (f) a C₁₋₆ alkyl group optionally substituted by 1 to 3        substituents selected from        -   (i) a hydroxy group, and        -   (ii) a C₁₋₆ alkoxy group,    -   (g) a C₁₋₆ alkoxy group optionally substituted by 1 to 3 halogen        atoms,    -   (h) a C₁₋₆ alkoxy-carbonyl group, and    -   (i) a C₆₋₁₄ aryl group optionally substituted by 1 to 3 halogen        atoms, or        R¹ is bonded to the atom on Ring A to form, together with Ring        A, a spiro ring substituted by oxo and optionally further        substituted by 1 to 3 C₁₋₆ alkyl groups.        [3] The compound or salt of [1] or [A], wherein

R¹ is

(1) a C₁₋₆ alkyl group optionally substituted by 1 to 3 substituentsselected from

-   -   (a) a cyano group,    -   (b) a C₆₋₁₄ aryl group optionally substituted by 1 to 3 C₁₋₆        alkoxy groups,    -   (c) a C₆₋₁₄ aryloxy group,    -   (d) a C₃₋₈ cycloalkyl group,    -   (e) a pyrazolyl group,    -   (f) an indazolyl group, and    -   (g) a dihydropyridyl group optionally substituted by 1 to 3 oxo        groups,        (2) a C₁₋₆ alkoxy group optionally substituted by 1 to 3 C₆₋₁₄        aryl groups,        (3) an amino group optionally mono- or di-substituted by        substituent(s) selected from    -   (a) a C₁₋₆ alkyl group optionally substituted by 1 to 3        substituents selected from        -   (i) a halogen atom,        -   (ii) a cyano group,        -   (iii) a C₃₋₈ cycloalkyl group,        -   (iv) a C₆₋₁₄ aryl group optionally substituted by 1 to 3            substituents selected from a halogen atom and a C₁₋₆ alkoxy            group,        -   (v) a pyridyl group, and        -   (vi) an oxetanyl group optionally substituted by 1 to 3 C₁₋₆            alkyl groups,    -   (b) a C₃₋₈ cycloalkyl group optionally substituted by 1 to 3        halogen atoms,    -   (c) a C₆₋₁₄ aryl group, and    -   (d) a tetrahydropyranyl group, an oxetanyl group, a        tetrahydrofuryl group and a pyrrolidinyl group, each of which is        optionally substituted by 1 to 3 C₁₋₆ alkyl groups,        (4) a C₃₋₈ cycloalkyl group optionally substituted by 1 to 3        C₆₋₁₄ aryl groups,        (5) a C₆₋₁₄ aryl group, or        (6) a 3- to 8-membered monocyclic non-aromatic heterocyclic        group or a 3,7-dioxa-9-azabicyclo[3.3.1]nonyl group, each of        which is optionally substituted by 1 to 5 substituents selected        from    -   (a) a halogen atom,    -   (b) a cyano group,    -   (c) a hydroxy group,    -   (d) an oxo group,    -   (e) a carbamoyl group optionally mono- or di-substituted by C₁₋₆        alkyl group(s),    -   (f) a C₁₋₆ alkyl group optionally substituted by 1 to 3        substituents selected from        -   (i) a hydroxy group, and        -   (ii) a C₁₋₆ alkoxy group,    -   (g) a C₁₋₆ alkoxy group optionally substituted by 1 to 3 halogen        atoms,    -   (h) a C₁₋₆ alkoxy-carbonyl group, and    -   (i) a C₆₋₁₄ aryl group optionally substituted by 1 to 3 halogen        atoms, or        R¹ is bonded to the atom on Ring A to form, together with Ring        A, a 2,8-diazaspiro[4.5]decane ring substituted by oxo and        optionally further substituted by 1 to 3 C₁₋₆ alkyl groups;

R² is

(1) a C₆₋₁₄ aryl group optionally substituted by 1 to 3 substituentsselected from

-   -   (a) a halogen atom, and    -   (b) a C₁₋₆ alkyl group optionally substituted by 1 to 3 halogen        atoms, or        (2) a 5- or 6-membered monocyclic aromatic heterocyclic group or        a 8- to 12-membered fused aromatic heterocyclic group, each of        which is optionally substituted by 1 to 3 substituents selected        from    -   (a) a halogen atom,    -   (b) a cyano group,    -   (c) a C₁₋₆ alkyl group optionally substituted by 1 to 3 halogen        atoms, and    -   (d) a C₃₋₈ cycloalkyl group;

X¹ is a carbon atom or a nitrogen atom;

R³ is

(1) a hydrogen atom, or(2) a halogen atom; and

Ring A is

(1)

each of which is optionally further substituted by 1 to 3 substituentsselected from

(a) a halogen atom,

(b) a C₁₋₆ alkyl group, and

(c) an oxo group, or

(2) a 8-azabicyclo[3.2.1]octane ring, a 2,5-diazabicyclo[2.2.1]heptanering or a 3-azabicyclo[3.1.0]hexane ring,(tert-butyl 4-(4-phenylpyrimidin-5-yl)piperazine-1-carboxylate isexcluded).[4] The compound or salt of any of [1], [3], [A] and [B], wherein R¹ is(1) a C₁₋₆ alkyl group optionally substituted by 1 to 3 substituentsselected from

-   -   (a) a cyano group,    -   (b) a C₆₋₁₄ aryl group optionally substituted by 1 to 3 C₁₋₆        alkoxy groups,    -   (c) a C₆₋₁₄ aryloxy group,    -   (d) a C₃₋₈ cycloalkyl group,    -   (e) a pyrazolyl group,    -   (f) an indazolyl group, and    -   (g) a dihydropyridyl group optionally substituted by 1 to 3 oxo        groups,        (2) a C₁₋₃ alkoxy group optionally substituted by 1 to 3 C₆₋₄        aryl groups,        (3) an amino group optionally mono- or di-substituted by        substituent(s) selected from    -   (a) a C₁₋₆ alkyl group optionally substituted by 1 to 3        substituents selected from        -   (i) a halogen atom,        -   (ii) a cyano group,        -   (iii) a C₃₋₈ cycloalkyl group,        -   (iv) a C₆₋₁₄ aryl group optionally substituted by 1 to 3            substituents selected from a halogen atom and a C₁₋₆ alkoxy            group,        -   (v) a pyridyl group, and        -   (vi) an oxetanyl group optionally substituted by 1 to 3 C₁₋₆            alkyl groups,    -   (b) a C₃₋₈ cycloalkyl group optionally substituted by 1 to 3        halogen atoms,    -   (c) a C₆₋₁₄ aryl group, and    -   (d) a tetrahydropyranyl group, an oxetanyl group, a        tetrahydrofuryl group and a pyrrolidinyl group, each of which is        optionally substituted by 1 to 3 C₁₋₆ alkyl groups,        (4) a C₃₋₈ cycloalkyl group optionally substituted by 1 to 3        C₆₋₁₄ aryl groups,        (5) a C₆₋₁₄ aryl group, or        (6) a 3- to 8-membered monocyclic non-aromatic heterocyclic        group or a 3,7-dioxa-9-azabicyclo[3.3.3.1]nonyl group, each of        which is optionally substituted by 1 to 5 substituents selected        from    -   (a) a halogen atom,    -   (b) a cyano group,    -   (c) a hydroxy group,    -   (d) an oxo group,    -   (e) a carbamoyl group optionally mono- or di-substituted by C₁₋₆        alkyl group(s),    -   (f) a C₁₋₆ alkyl group optionally substituted by 1 to 3        substituents selected from        -   (i) a hydroxy group, and        -   (ii) a C₁₋₆ alkoxy group,    -   (g) a C₁₋₆ alkoxy group optionally substituted by 1 to 3 halogen        atoms,    -   (h) a C₁₋₆ alkoxy-carbonyl group, and    -   (i) a C₆₋₁₄ aryl group optionally substituted by 1 to 3 halogen        atoms, or        R¹ is bonded to the atom on Ring A to form, together with Ring        A, a 2,8-diazaspiro[4.5]decane ring substituted by oxo and        optionally further substituted by 1 to 3 C₁₋₆ alkyl groups.        [C] The compound or salt of [1] or [2], wherein

R¹ is a 3- to 8-membered monocyclic non-aromatic heterocyclic groupoptionally substituted by 1 to 5 substituents selected from

-   -   (a) a halogen atom,    -   (b) a cyano group,    -   (c) a carbamoyl group,    -   (d) a C₁₋₆ alkyl group optionally substituted by 1 to 3 C₁₋₆        alkoxy groups, and    -   (e) a C₁₋₆ alkoxy group;

R² is

(1) a C₆₋₁₄ aryl group optionally substituted by 1 to 3 substituentsselected from

-   -   (a) a halogen atom, and    -   (b) a C₁₋₆ alkyl group optionally substituted by 1 to 3 halogen        atoms, or        (2) a 5- or 6-membered monocyclic aromatic heterocyclic group        optionally substituted by 1 to 3 substituents selected from

(a) a halogen atom, and

(b) a C₁₋₆ alkyl group;

X¹ is a carbon atom;

R³ is a hydrogen atom; and

Ring A is

[D] The compound or salt of any of [1], [3] and [A], wherein

R¹ is

(1) a C₁₋₆ alkyl group optionally substituted by 1 to 3 substituentsselected from

-   -   (a) a cyano group,    -   (b) a phenyl group optionally substituted by 1 to 3 C₁₋₆ alkoxy        groups,    -   (c) a phenoxy group,    -   (d) a cyclopropyl group,    -   (e) a pyrazolyl group,    -   (f) an indazolyl group, and    -   (g) a dihydropyridyl group optionally substituted by 1 to 3 oxo        groups,        (2) a C₁₋₆ alkoxy group optionally substituted by 1 to 3 phenyl        groups,        (3) an amino group optionally mono- or di-substituted by        substituent(s) selected from    -   (a) a C₁₋₆ alkyl group optionally substituted by 1 to 3        substituents selected from        -   (i) a halogen atom,        -   (ii) a cyano group,        -   (iii) a cyclopropyl group,        -   (iv) a cyclobutyl group,        -   (v) a phenyl group optionally substituted by 1 to 3            substituents selected from a halogen atom and a C₁₋₆ alkoxy            group,        -   (vi) a pyridyl group, and        -   (vii) an oxetanyl group optionally substituted by 1 to 3            C₁₋₆ alkyl groups,    -   (b) a cyclopropyl group, a cyclobutyl group and a cyclopentyl        group, each of which is optionally substituted by 1 to 3 halogen        atoms,    -   (c) a phenyl group, and    -   (d) a tetrahydropyranyl group, an oxetanyl group, a        tetrahydrofuryl group and a pyrrolidinyl group, each of which is        optionally substituted by 1 to 3 C₁₋₆ alkyl groups,        (4) a cyclopropyl group optionally substituted by 1 to 3 phenyl        groups,        (5) a phenyl group, or        (6) an azetidinyl group, a pyrrolidinyl group, a piperidyl        group, a piperazinyl group, a morpholinyl group, a        1,1-dioxidothiomorpholinyl group, a tetrahydropyranyl group, a        3-oxa-6-azabicyclo[3.1.1]heptyl group, an        8-oxa-3-azabicyclo[3.2.1]octyl group, a        2-oxa-5-azabicyclo[2.2.1]heptyl group, a        3-oxa-8-azabicyclo[3.2.1]octyl group, a        6-oxa-3-azabicyclo[3.1.1]heptyl group or a        3,7-dioxa-9-azabicyclo[3.3.1]nonyl group, each of which is        optionally substituted by 1 to 5 substituents selected from    -   (a) a halogen atom,    -   (b) a cyano group,    -   (c) a hydroxy group,    -   (d) an oxo group,    -   (e) a carbamoyl group optionally mono- or di-substituted by C₁₋₆        alkyl group(s),    -   (f) a C₁₋₆ alkyl group optionally substituted by 1 to 3        substituents selected from        -   (i) a hydroxy group, and        -   (ii) a C₁₋₆ alkoxy group,    -   (g) a C₁₋₆ alkoxy group optionally substituted by 1 to 3 halogen        atoms,    -   (h) a C₁₋₆ alkoxy-carbonyl group, and    -   (i) a phenyl group optionally substituted by 1 to 3 halogen        atoms, or        R¹ is bonded to the atom on Ring A to form, together with Ring        A, a 2,8-diazaspiro[4.5]decane ring substituted by oxo and        optionally further substituted by 1 to 3 C₁₋₆ alkyl groups;

R² is

(1) a phenyl group optionally substituted by 1 to 3 substituentsselected from

-   -   (a) a halogen atom, and    -   (b) a C₁₋₆ alkyl group optionally substituted by 1 to 3 halogen        atoms, or        (2) a pyrazolyl group, an oxazolyl group, a thiazolyl group, a        thiadiazolyl group, a pyridyl group, an indazolyl group or a        benzothiazolyl group, each of which is optionally substituted by        1 to 3 substituents selected from    -   (a) a halogen atom,    -   (b) a cyano group,    -   (c) a C₁₋₆ alkyl group optionally substituted by 1 to 3 halogen        atoms, and    -   (d) a cyclopropyl group;

X¹ is a carbon atom or a nitrogen atom;

R³ is

(1) a hydrogen atom, or(2) a halogen atom; and

Ring A is

(1)

each of which is optionally further substituted by 1 to 3 substituentsselected from

(a) a halogen atom,

(b) a C₁₋₆ alkyl group, and

(c) an oxo group, or

(2) a 8-azabicyclo[3.2.1]octane ring, a 2,5-diazabicyclo[2.2.1]heptanering or a 3-azabicyclo[3.1.0]hexane ring,(tert-butyl 4-(4-phenylpyrimidin-5-yl)piperazine-1-carboxylate isexcluded).[E] The compound or salt of any of [1], [3], [4], [A], [B] and [D],wherein R¹ is(1) a C₁₋₆ alkyl group optionally substituted by 1 to 3 substituentsselected from

-   -   (a) a cyano group,    -   (b) a phenyl group optionally substituted by 1 to 3 C₁₋₆ alkoxy        groups,    -   (c) a phenoxy group,    -   (d) a cyclopropyl group,    -   (e) a pyrazolyl group,    -   (f) an indazolyl group, and    -   (g) a dihydropyridyl group optionally substituted by 1 to 3 oxo        groups,        (2) a C₁₋₃ alkoxy group optionally substituted by 1 to 3 phenyl        groups,        (3) an amino group optionally mono- or di-substituted by        substituent(s) selected from    -   (a) a C₁₋₆ alkyl group optionally substituted by 1 to 3        substituents selected from        -   (i) a halogen atom,        -   (ii) a cyano group,        -   (iii) a cyclopropyl group,        -   (iv) a cyclobutyl group,        -   (v) a phenyl group optionally substituted by 1 to 3            substituents selected from a halogen atom and a C₁₋₆ alkoxy            group,        -   (vi) a pyridyl group, and        -   (vii) an oxetanyl group optionally substituted by 1 to 3            C₁₋₆ alkyl groups,    -   (b) a cyclopropyl group, a cyclobutyl group and a cyclopentyl        group, each of which is optionally substituted by 1 to 3 halogen        atoms,    -   (c) a phenyl group, and    -   (d) a tetrahydropyranyl group, an oxetanyl group, a        tetrahydrofuryl group and a pyrrolidinyl group, each of which is        optionally substituted by 1 to 3 C₁₋₆ alkyl groups,        (4) a cyclopropyl group optionally substituted by 1 to 3 phenyl        groups,        (5) a phenyl group, or        (6) an azetidinyl group, a pyrrolidinyl group, a piperidyl        group, a piperazinyl group, a morpholinyl group, a        1,1-dioxidothiomorpholinyl group, a tetrahydropyranyl group, a        3-oxa-6-azabicyclo[3.1.1]heptyl group, an        8-oxa-3-azabicyclo[3.2.1]octyl group, a        2-oxa-5-azabicyclo[2.2.1]heptyl group, a        3-oxa-8-azabicyclo[3.2.1]octyl group, a        6-oxa-3-azabicyclo[3.1.1]heptyl group or a        3,7-dioxa-9-azabicyclo[3.3.1]nonyl group, each of which is        optionally substituted by 1 to 5 substituents selected from    -   (a) a halogen atom,    -   (b) a cyano group,    -   (c) a hydroxy group,    -   (d) an oxo group,    -   (e) a carbamoyl group optionally mono- or di-substituted by C₁₋₆        alkyl group(s),    -   (f) a C₁₋₆ alkyl group optionally substituted by 1 to 3        substituents selected from        -   (i) a hydroxy group, and        -   (ii) a C₁₋₆ alkoxy group,    -   (g) a C₁₋₆ alkoxy group optionally substituted by 1 to 3 halogen        atoms,    -   (h) a C₁₋₆ alkoxy-carbonyl group, and    -   (i) a phenyl group optionally substituted by 1 to 3 halogen        atoms, or        R¹ is bonded to the atom on Ring A to form, together with Ring        A, a 2,8-diazaspiro[4.5]decane ring substituted by oxo and        optionally further substituted by 1 to 3 C₁₋₆ alkyl groups.        [5] The compound or salt of any of [1]-[4], [A], [B], [D] and        [E], wherein

R¹ is

(1) an amino group optionally mono- or di-substituted by substituent(s)selected from

-   -   (a) a C₁₋₆ alkyl group optionally substituted by 1 to 3        substituents selected from        -   (i) a halogen atom, and        -   (ii) a phenyl group optionally substituted by 1 to 3 halogen            atoms,    -   (b) a tetrahydropyranyl group, and    -   (c) a tetrahydrofuryl group, or        (2) an azetidinyl group or a pyrrolidinyl group, each of which        is optionally substituted by 1 to 5 substituents selected from    -   (a) a halogen atom,    -   (b) a cyano group,    -   (c) a carbamoyl group,    -   (d) a C₁₋₆ alkyl group, and    -   (e) a C₁₋₆ alkoxy group;

R² is

(1) a phenyl group optionally substituted by 1 to 3 halogen atoms, or(2) a pyrazolyl group, a thiazolyl group or a thiadiazolyl group, eachof which is optionally substituted by 1 to 3 substituents selected from

(a) a halogen atom,

(b) a C₁₋₆ alkyl group, and

(c) a cyclopropyl group;

X¹ is a carbon atom or a nitrogen atom;

R³ is a hydrogen atom; and

Ring A is

[F] The compound or salt of any of [1]-[5], [A], [B], [D] and [E],wherein

R¹ is

(1) an amino group optionally mono- or di-substituted by substituent(s)selected from

-   -   (a) a C₁₋₆ alkyl group optionally substituted by 1 to 3        substituents selected from        -   (i) a halogen atom, and        -   (ii) a phenyl group optionally substituted by 1 to 3 halogen            atoms,    -   (b) a tetrahydropyranyl group, and    -   (c) a tetrahydrofuryl group, or        (2) an azetidinyl group or a pyrrolidinyl group, each of which        is optionally substituted by 1 to 5 substituents selected from

(a) a halogen atom, and

(b) a cyano group;

R² is

(1) a phenyl group optionally substituted by 1 to 3 halogen atoms, or(2) a pyrazolyl group or a thiazolyl group, each of which is optionallysubstituted by 1 to 3 substituents selected from

(a) a halogen atom,

(b) a C₁₋₆ alkyl group, and

(c) a cyclopropyl group;

X¹ is a carbon atom or a nitrogen atom;

R³ is a hydrogen atom; and

Ring A is

[G] The compound or salt of any of [1]-[5], [A], [B] and [D]-[F],wherein

R¹ is

(1) an amino group optionally mono- or di-substituted by substituent(s)selected from

-   -   (a) a C₁₋₆ alkyl group optionally substituted by 1 to 3        substituents selected from        -   (i) a halogen atom, and        -   (ii) a phenyl group optionally substituted by 1 to 3 halogen            atoms,    -   (b) a tetrahydropyranyl group, and    -   (c) a tetrahydrofuryl group, or        (2) an azetidinyl group or a pyrrolidinyl group, each of which        is optionally substituted by 1 to 3 halogen atoms;

R² is

(1) a phenyl group optionally substituted by 1 to 3 halogen atoms, or(2) a pyrazolyl group or a thiazolyl group, each of which is optionallysubstituted by 1 to 3 substituents selected from

(a) a halogen atom,

(b) a C₁₋₆ alkyl group, and

(c) a cyclopropyl group;

X¹ is a carbon atom or a nitrogen atom;

R³ is a hydrogen atom; and

Ring A is

[H] The compound or salt of any of [1], [2] and [C], wherein

R¹ is a pyrrolidinyl group optionally substituted by 1 to 5 substituentsselected from

-   -   (a) a halogen atom,    -   (b) a cyano group,    -   (c) a carbamoyl group,    -   (d) a C₁₋₆ alkyl group optionally substituted by 1 to 3 C₁₋₆        alkoxy groups, and    -   (e) a C₁₋₆ alkoxy group;

R² is

(1) a phenyl group optionally substituted by 1 to 3 substituentsselected from

-   -   (a) a halogen atom, and    -   (b) a C₁₋₆ alkyl group optionally substituted by 1 to 3 halogen        atoms, or        (2) a pyrazolyl group, a thiadiazolyl group or a pyridyl group,        each of which is optionally substituted by 1 to 3 substituents        selected from

(a) a halogen atom, and

(b) a C₁₋₆ alkyl group;

X¹ is a carbon atom;

R³ is a hydrogen atom; and

Ring A is

[I] The compound or salt of any of [1]-[5], [A], [B], [D] and [E],wherein

R¹ is a pyrrolidinyl group optionally substituted by 1 to 5 substituentsselected from

(a) a halogen atom,

(b) a cyano group,

(c) a carbamoyl group,

(d) a C₁₋₆ alkyl group, and

(e) a C₁₋₆ alkoxy group;

R² is a pyrazolyl group or a thiadiazolyl group, each of which isoptionally substituted by 1 to 3 substituents selected from

(a) a halogen atom, and

(b) a C₁₋₆ alkyl group;

X¹ is a carbon atom;

R³ is a hydrogen atom; and

Ring A is

[6] The compound or salt of any of [1]-[5], [A], [B], [D]-[F] and [I],wherein

R¹ is a pyrrolidinyl group optionally substituted by 1 to 5 substituentsselected from

(a) a halogen atom, and

(b) a cyano group;

R² is a pyrazolyl group optionally substituted by 1 to 3 substituentsselected from

(a) a halogen atom, and

(b) a C₁₋₆ alkyl group;

X¹ is a carbon atom;

R³ is a hydrogen atom; and

Ring A is

[J] The compound or salt of any of [1], [3], [A] and [D], wherein

R¹ is

(1) a C₁₋₆ alkyl group optionally substituted by 1 to 3 substituentsselected from

(a) a cyclopropyl group, and

(b) an indazolyl group,

(2) a C₁₋₆ alkoxy group optionally substituted by 1 to 3 phenyl groups,(3) an amino group optionally mono- or di-substituted by substituent(s)selected from

-   -   (a) a C₁₋₆ alkyl group optionally substituted by 1 to 3        substituents selected from        -   (i) a halogen atom,        -   (ii) a phenyl group optionally substituted by 1 to 3 halogen            atoms,        -   (iii) a pyridyl group, and        -   (iv) an oxetanyl group optionally substituted by 1 to 3 C₁₋₆            alkyl groups,    -   (b) a cyclopropyl group,    -   (c) a cyclopentyl group,    -   (d) a tetrahydropyranyl group,    -   (e) a tetrahydrofuryl group, and    -   (f) a phenyl group,        (4) a cyclopropyl group, or        (5) an azetidinyl group, a pyrrolidinyl group, a        1,1-dioxidothiomorpholinyl group or a        3-oxa-6-azabicyclo[3.1.1]heptyl group, each of which is        optionally substituted by 1 to 5 substituents selected from    -   (a) a halogen atom,    -   (b) a cyano group,    -   (c) a carbamoyl group,    -   (d) a C₁₋₆ alkyl group optionally substituted by 1 to 3 C₁₋₆        alkoxy groups,    -   (e) a C₁₋₆ alkoxy group, and    -   (f) a phenyl group optionally substituted by 1 to 3 halogen        atoms, or        R¹ is bonded to the atom on Ring A to form, together with Ring        A, a 2,8-diazaspiro[4.5]decane ring substituted by oxo and        optionally further substituted by 1 to 3 C₁₋₆ alkyl groups;

R² is

(1) a phenyl group optionally substituted by 1 to 3 substituentsselected from

(a) a halogen atom, and

(b) a C₁₋₆ alkyl group, or

(2) a pyrazolyl group, an oxazolyl group, a thiazolyl group, athiadiazolyl group, a pyridyl group or a benzothiazolyl group, each ofwhich is optionally substituted by 1 to 3 substituents selected from

-   -   (a) a halogen atom,    -   (b) a cyano group,    -   (c) a C₁₋₆ alkyl group optionally substituted by 1 to 3 halogen        atoms, and    -   (d) a cyclopropyl group;

X¹ is a carbon atom or a nitrogen atom;

R³ is

(1) a hydrogen atom, or(2) a halogen atom; and

Ring A is

(1)

each of which is optionally further substituted by 1 to 3 substituentsselected from

(a) a halogen atom, and

(b) a C₁₋₆ alkyl group, or

(2) a 8-azabicyclo[3.2.1]octane ring or a 2,5-diazabicyclo[2.2.1]heptanering.[K] The compound or salt of any of [1]-[4], [A], [B], [D] and [E],wherein

R¹ is a pyrrolidinyl group optionally substituted by 1 to 3 substituentsselected from

-   -   (a) a halogen atom,    -   (b) a cyano group,    -   (c) a carbamoyl group, and    -   (d) a C₁₋₆ alkyl group optionally substituted by 1 to 3 C₁₋₆        alkoxy groups;

R² is a pyrazolyl group, a thiazolyl group, a thiadiazolyl group or apyridyl group, each of which is optionally substituted by 1 to 3substituents selected from

(a) a halogen atom, and

(b) a C₁₋₆ alkyl group;

X¹ is a carbon atom;

R³ is a hydrogen atom; and

Ring A is

-   (2R)-1-((1-(4-(4-methyl-1H-pyrazol-1-yl)pyridin-3-yl)piperidin-4-yl)carbonyl)pyrrolidine-2-carbonitrile    or a salt thereof,-   (2R)-1-((1-(4-(4-chloro-1H-pyrazol-1-yl)pyridin-3-yl)piperidin-4-yl)carbonyl)pyrrolidine-2-carbonitrile    or a salt thereof,-   (2R)-4,4-difluoro-1-((1-(4-(4-methyl-1H-pyrazol-1-yl)pyridin-3-yl)piperidin-4-yl)carbonyl)pyrrolidine-2-carbonitrile    or a salt thereof,-   (3-fluoroazetidin-1-yl)(1-(4-(4-fluorophenyl)pyrimidin-5-yl)piperidin-4-yl)methanone    or a salt thereof,-   (1-(4-(4-chloro-1H-pyrazol-1-yl)pyridin-3-yl)piperidin-4-yl)(3-fluoroazetidin-1-yl)methanone    or a salt thereof,-   (1-(4-(4-chloro-1H-pyrazol-1-yl)pyridin-3-yl)piperidin-4-yl)((3S)-3-fluoropyrrolidin-1-yl)methanone    or a salt thereof,-   (1-(4-(4-fluorophenyl)pyrimidin-5-yl)piperidin-4-yl)((3S)-3-fluoropyrrolidin-1-yl)methanone    or a salt thereof,-   N-benzyl-N-(2-fluoroethyl)-4-(4-phenylpyrimidin-5-yl)piperazine-1-carboxamide    or a salt thereof,-   N-(4-fluorobenzyl)-N-(2-fluoroethyl)-4-(4-(4-methyl-1H-pyrazol-1-yl)pyridin-3-yl)piperazine-1-carboxamide    or a salt thereof,-   ((3S)-3-fluoropyrrolidin-1-yl)(1-(4-(5-methyl-1,    3-thiazol-2-yl)pyridin-3-yl)piperidin-4-yl)methanone or a salt    thereof,-   (3-fluoroazetidin-1-yl)(1-(4-(5-methyl-1,3-thiazol-2-yl)pyridin-3-yl)piperidin-4-yl)methanone    or a salt thereof,-   (1-(4-(4-bromo-1H-pyrazol-1-yl)pyridin-3-yl)piperidin-4-yl)(3-fluoroazetidin-1-yl)methanone    or a salt thereof, or-   (1-(4-(4-cyclopropyl-1H-pyrazol-1-yl)pyridin-3-yl)piperidin-4-yl)(3-fluoroazetidin-1-yl)methanone    or a salt thereof.    [8]    (2R)-1-((1-(4-(4-methyl-1H-pyrazol-1-yl)pyridin-3-yl)piperidin-4-yl)carbonyl)pyrrolidine-2-carbonitrile    or a salt thereof.    [9]    (2R)-1-((1-(4-(4-chloro-1H-pyrazol-1-yl)pyridin-3-yl)piperidin-4-yl)carbonyl)pyrrolidine-2-carbonitrile    or a salt thereof.    [10]    (2R)-4,4-difluoro-1-((1-(4-(4-methyl-1H-pyrazol-1-yl)pyridin-3-yl)piperidin-4-yl)carbonyl)pyrrolidine-2-carbonitrile    or a salt thereof.    [11] A medicament comprising the compound or salt of any of    [1]-[10].    [12] The medicament of [11], which is a cholesterol 24-hydroxylase    inhibitor.    [13] The medicament of [11], which is an agent for the prophylaxis    or treatment of epilepsy or neurodegenerative disease.    [14] The medicament of [13], wherein the neurodegenerative disease    is Alzheimer's disease, mild cognitive disorder, Huntington's    disease, Parkinson's disease or multiple sclerosis.    [15] The compound or salt of any of [1]-[10] for use in the    prophylaxis or treatment of epilepsy or neurodegenerative disease.    [16] The compound or salt of [15], wherein the neurodegenerative    disease is Alzheimer's disease, mild cognitive disorder,    Huntington's disease, Parkinson's disease or multiple sclerosis.    [17] A method of inhibiting cholesterol 24-hydroxylase in a mammal,    which comprises administering an effective amount of the compound or    salt of any of [1]-[10] to the mammal.    [18] A method for the prophylaxis or treatment of epilepsy or    neurodegenerative disease, which comprises administering an    effective amount of the compound or salt of any of [1]-[10] to the    mammal.    [19] The method of [18], wherein the neurodegenerative disease is    Alzheimer's disease, mild cognitive disorder, Huntington's disease,    Parkinson's disease or multiple sclerosis.    [20] Use of the compound or salt of any of [1]-[10] for the    production of an agent for the prophylaxis or treatment of epilepsy    or neurodegenerative disease.    [21] The use of [20], wherein the neurodegenerative disease is    Alzheimer's disease, mild cognitive disorder, Huntington's disease,    Parkinson's disease or multiple sclerosis.

Effect of the Invention

Compound (I) has a superior CH24H inhibitory action, which is useful asan agent for the prophylaxis or treatment of epilepsy, neurodegenerativedisease (e.g., Alzheimer's disease, mild cognitive disorder,Huntington's disease, Parkinson's disease, multiple sclerosis,amyotrophic lateral sclerosis, traumatic brain injury, cerebralinfarction, glaucoma and the like), schizophrenia and the like.

DETAILED DESCRIPTION OF THE INVENTION

In the present specification, the “halogen atom” means a fluorine atom,a chlorine atom, a bromine atom or an iodine atom.

In the present specification, the “C₁₋₁₀ alkyl group” means, forexample, methyl, ethyl, propyl, isopropyl, butyl, 2-methylpropyl,1-methylpropyl, tert-butyl, pentyl, isopentyl, neo-pentyl,1-ethylpropyl, hexyl, isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl,3,3-dimethylbutyl, 2-ethylbutyl, heptyl, octyl, nonyl, decyl or thelike. Among them, a C₁₋₆ alkyl group is preferable.

In the present specification, the “C₁₋₆ alkyl (group)” means, forexample, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl,tert-butyl, pentyl, isopentyl, neopentyl, 1-ethylpropyl, hexyl,isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl,2-ethylbutyl or the like.

In the present specification, the “C₂₋₁₀ alkenyl group” means, forexample, vinyl, 1-propenyl, 2-propenyl, 2-methyl-1-propenyl, 1-butenyl,2-butenyl, 3-butenyl, 3-methyl-2-butenyl, 1-pentenyl, 2-pentenyl,3-pentenyl, 4-pentenyl, 4-methyl-3-pentenyl, 1-hexenyl, 3-hexenyl,5-hexenyl, 1-heptenyl, 1-octenyl or the like. Among them, a C₂₋₆ alkenylgroup is preferable.

In the present specification, the “C₂₋₆ alkenyl (group)” means, forexample, vinyl, 1-propenyl, 2-propenyl, 2-methyl-1-propenyl, 1-butenyl,2-butenyl, 3-butenyl, 3-methyl-2-butenyl, 1-pentenyl, 2-pentenyl,3-pentenyl, 4-pentenyl, 4-methyl-3-pentenyl, 1-hexenyl, 3-hexenyl,5-hexenyl or the like.

In the present specification, the “C₂₋₁₀ alkynyl group” means, forexample, ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl,3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl,1,1-dimethylprop-2-yn-1-yl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl,5-hexynyl, 1-heptynyl, 1-octynyl or the like. Among them, a C₁₋₆ alkynylgroup is preferable.

In the present specification, the “C₂₋₆ alkynyl (group)” means, forexample, ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl,3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl,1,1-dimethylprop-2-yn-1-yl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl,5-hexynyl or the like.

In the present specification, the “C₁₋₆ alkoxy (group)” means, forexample, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy,sec-butoxy, tert-butoxy, pentyloxy, isopentyloxy, hexyloxy or the like.

In the present specification, the “C₁₋₃ alkoxy group” means, methoxy,ethoxy, propoxy or isopropoxy.

In the present specification, the “C₂₋₆ alkenyloxy (group)” means, forexample, vinyloxy, 1-propenyloxy, 2-propenyloxy, 2-methyl-1-propenyloxy,1-butenyloxy, 2-butenyloxy, 3-butenyloxy, 3-methyl-2-butenyloxy,1-pentenyloxy, 2-pentenyloxy, 3-pentenyloxy, 4-pentenyloxy,4-methyl-3-pentenyloxy, 1-hexenyloxy, 3-hexenyloxy, 5-hexenyloxy or thelike.

In the present specification, the “C₂₋₆ alkynyloxy (group)” means, forexample, ethynyloxy, 1-propynyloxy, 2-propynyloxy, 1-butynyloxy,2-butynyloxy, 3-butynyloxy, 1-pentynyloxy, 2-pentynyloxy, 3-pentynyloxy,4-pentynyloxy, 1,1-dimethylprop-2-yn-1-yloxy, 1-hexynyloxy,2-hexynyloxy, 3-hexynyloxy, 4-hexynyloxy, 5-hexynyloxy or the like.

In the present specification, the “C₁₋₆ alkylenedioxy (group)” means,for example, methylenedioxy, ethylenedioxy or the like.

In the present specification, the “C₁₋₆ alkoxy-carbonyl (group)” means,for example, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl,isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl,tert-butoxycarbonyl or the like.

In the present specification, the “C₁₋₆ alkyl-carbonyl (group)” means,for example, acetyl, propanoyl, butanoyl, 2-methylpropanoyl or the like.

In the present specification, the “mono-C₁₋₆ alkylamino (group)” means,for example, methylamino, ethylamino, propylamino, isopropylamino,butylamino, isobutylamino, tert-butylamino or the like.

In the present specification, the “di-C₁₋₆ alkylamino (group)” means,for example, dimethylamino, diethylamino, dipropylamino,diisopropylamino, dibutylamino, diisobutylamino, ditert-butylamino orthe like.

In the present specification, the “C₃₋₁₀ cycloalkyl group” means, forexample, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,cyclooctyl, cyclononyl, cyclodecyl or the like. Among them, a C₃₋₆cycloalkyl group is preferable.

In the present specification, the “C₃₋₈ cycloalkyl (group)” means, forexample, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,cyclooctyl or the like.

In the present specification, the “C₃₋₆ cycloalkyl (group)” means, forexample, those having 3 to 6 carbon atoms from among the above-mentionedC₃₋₈ cycloalkyl (group).

In the present specification, the “C₃₋₈ cycloalkyloxy (group)” means,for example, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy,cyclohexyloxy, cycloheptyloxy, cyclooctyloxy or the like.

In the present specification, the “C₃₋₆ cycloalkyloxy (group)” means,for example, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy,cyclohexyloxy or the like.

In the present specification, the “C₃₋₁₀ cycloalkenyl (group)” means,for example, cyclopropenyl (e.g., 2-cyclopropen-1-yl), cyclobutenyl(e.g., 2-cyclobuten-1-yl), cyclopentenyl (e.g., 2-cyclopenten-1-yl,3-cyclopenten-1-yl), cyclohexenyl (e.g., 1-cyclohexen-1-yl,2-cyclohexen-1-yl, 3-cyclohexen-1-yl), cycloheptenyl (e.g.,1-cyclopenten-1-yl, 2-cyclohepten-1-yl, 2-cyclohepten-1-yl),cyclooctenyl (e.g., 1-cyclohepten-1-yl, 2-cyclohepten-1-yl,3-cyclohepten-1-yl), cyclononenyl (e.g., 1-cyclononen-1-yl,2-cyclononen-1-yl, 3-cyclononen-1-yl) or the like. Among them, a C₃₋₈cycloalkenyl group is preferable.

In the present specification, the “C₃₋₈ cycloalkenyl (group)” means, forexample, cyclopropenyl (e.g., 2-cyclopropen-1-yl), cyclobutenyl (e.g.,2-cyclobuten-1-yl), cyclopentenyl (e.g., 2-cyclopenten-1-yl,3-cyclopenten-1-yl), cyclohexenyl (e.g., 2-cyclohexen-1-yl,3-cyclohexen-1-yl) or the like.

In the present specification, the “C₃₋₈ cycloalkenyloxy (group)” means,for example, cyclopropenyloxy (e.g., 2-cyclopropen-1-yloxy),cyclobutenyloxy (e.g., 2-cyclobuten-1-yloxy), cyclopentenyloxy (e.g.,2-cyclopenten-1-yloxy, 3-cyclopenten-1-yloxy), cyclohexenyloxy (e.g.,2-cyclohexen-1-yloxy, 3-cyclohexen-1-yloxy) or the like.

In the present specification, the “C₄₋₁₀ cycloalkadienyl group” means,for example, 1,3-cyclobutadien-1-yl, 1,3-cyclopentadien-1-yl,1,4-cyclopentadien-1-yl, 2,4-cyclopentadien-1-yl,1,3-cyclohexadien-1-yl, 1,4-cyclohexadien-1-yl, 1,5-cyclohexadien-1-yl,2,4-cyclohexadien-1-yl, 2,5-cyclohexadien-1-yl, 1,3-cyclooctadien-1-yl,1,4-cyclooctadien-1-yl, 1,5-cyclooctadien-1-yl, 1,6-cyclooctadien-1-yl,1,7-cyclooctadien-1-yl, 2,4-cyclooctadien-1-yl, 2,5-cyclooctadien-1-yl,2,6-cyclooctadien-1-yl, 2,7-cyclooctadien-1-yl, 3,5-cyclooctadien-1-yl,3,6-cyclooctadien-1-yl or the like. Among them, a C₄₋₆ cycloalkadienylgroup is preferable.

In the present specification, the “C₄₋₆ cycloalkadienyl group” means,for example, 1,3-cyclobutadien-1-yl, 1,3-cyclopentadien-1-yl,1,4-cyclopentadien-1-yl, 2,4-cyclopentadien-1-yl,1,3-cyclohexadien-1-yl, 1,4-cyclohexadien-1-yl, 1,5-cyclohexadien-1-yl,2,4-cyclohexadien-1-yl, 2,5-cyclohexadien-1-yl or the like.

The above-mentioned C₃₋₁₀ cycloalkyl group, C₃₋₁₀ cycloalkenyl group andC₄₋₁₀ cycloalkadienyl group are each optionally fused with a benzenering to form a fused ring group, and examples of the fused ring groupinclude indanyl, dihydronaphthyl, tetrahydronaphthyl, fluorenyl and thelike.

The above-mentioned C₃₋₁₀ cycloalkyl group, C₃₋₁₀ cycloalkenyl group andC₄₋₁₀ cycloalkadienyl group may be a C₇₋₁₀ bridged hydrocarbon group.Examples of the C₇₋₁₀ bridged hydrocarbon group includebicyclo[2.2.1]heptyl(norbornyl), bicyclo[2.2.2]octyl,bicyclo[3.2.1]octyl, bicyclo[3.2.2]nonyl, bicyclo[3.3.1]nonyl,bicyclo[4.2.1]nonyl, bicyclo[4.3.1]decyl, adamantyl and the like.

The above-mentioned C₃₋₁₀ cycloalkyl group, C₃₋₁₀ cycloalkenyl group andC₄₋₁₀ cycloalkadienyl group are each optionally form a spiro ring groupwith a C₃₋₁₀ cycloalkane, a C₃₋₁₀ cycloalkene or a C₄₋₁₀ cycloalkadiene.Examples of the C₃₋₁₀ cycloalkane, C₃₋₁₀ cycloalkene and C₄₋₁₀cycloalkadiene include rings corresponding to the above-mentioned C₃₋₁₀cycloalkyl group, C₃₋₁₀ cycloalkenyl group and C₄₋₁₀ cycloalkadienylgroup. Examples of the spiro ring group include spiro[4.5]decan-8-yl andthe like.

In the present specification, the “C₆₋₁₄ aryl (group)” means, forexample, phenyl, 1-naphthyl, 2-naphthyl or the like.

In the present specification, the “C₆₋₁₄ aryloxy (group)” means, forexample, phenoxy, 1-naphthyloxy, 2-naphthyloxy or the like.

In the present specification, the “C₇₋₁₄ aralkyl (group)” means, forexample, benzyl, phenethyl or the like.

In the present specification, the “C₇₋₁₄ aralkyloxy (group)” means, forexample, benzyloxy, phenethyloxy or the like.

In the present specification, the “C₈₋₁₃ arylalkenyl (group)” means, forexample, styryl or the like.

In the present specification, the “hydrocarbon group” means, forexample, a C₁₋₁₀ alkyl group, a C₂₋₁₀ alkenyl group, a C₂₋₁₀ alkynylgroup, a C₃₋₁₀ cycloalkyl group, a C₃₋₁₀ cycloalkenyl group, a C₄₋₁₀cycloalkadienyl group, a C₆₋₁₄ aryl group, a C₇₋₁₄ aralkyl group, aC₈₋₁₃ arylalkenyl group or the like.

In the present specification, the “heterocyclic group” means an aromaticheterocyclic group or a non-aromatic heterocyclic group.

In the present specification, the “aromatic heterocyclic group” means amonocyclic aromatic heterocyclic group or a fused aromatic heterocyclicgroup, for example, a 5- to 12-membered aromatic heterocyclic group,specifically a 5- to 7-membered monocyclic aromatic heterocyclic groupor a 8- to 12-membered fused aromatic heterocyclic group.

In the present specification, examples of the “monocyclic aromaticheterocyclic group” include a 5- to 7-membered (preferably 5- or6-membered) monocyclic aromatic heterocyclic group containing, as aring-constituting atom besides carbon atoms, 1 to 4 hetero atomsselected from an oxygen atom, a sulfur atom (optionally oxidized) and anitrogen atom (optionally oxidized). Examples thereof include furyl(e.g., 2-furyl, 3-furyl), thienyl (e.g., 2-thienyl, 3-thienyl), pyridyl(e.g., 2-pyridyl, 3-pyridyl, 4-pyridyl), pyrimidinyl (e.g.,2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl), pyridazinyl (e.g.,3-pyridazinyl, 4-pyridazinyl), pyrazinyl (e.g., 2-pyrazinyl), pyrrolyl(e.g., 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl), imidazolyl (e.g.,1-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl), pyrazolyl(e.g., 1-pyrazolyl, 3-pyrazolyl, 4-pyrazolyl), thiazolyl (e.g.,2-thiazolyl, 4-thiazolyl, 5-thiazolyl), isothiazolyl (e.g.,3-isothiazolyl, 4-isothiazolyl, 5-isothiazolyl), oxazolyl (e.g.,2-oxazolyl, 4-oxazolyl, 5-oxazolyl), isoxazolyl (e.g., 3-isoxazolyl,4-isoxazolyl, 5-isoxazolyl), oxadiazolyl (e.g., 1,2,4-oxadiazol-5-yl,1,3,4-oxadiazol-2-yl), thiadiazolyl (e.g., 1,3,4-thiadiazol-2-yl),triazolyl (e.g., 1,2,4-triazol-1-yl, 1,2,4-triazol-3-yl,1,2,3-triazol-1-yl, 1,2,3-triazol-2-yl, 1,2,3-triazol-4-yl), tetrazolyl(e.g., tetrazol-1-yl, tetrazol-5-yl), triazinyl (e.g.,1,2,4-triazin-1-yl, 1,2,4-triazin-3-yl) and the like.

In the present specification, examples of the “fused aromaticheterocyclic group” include an 8- to 12-membered fused aromaticheterocyclic group, specifically, a group derived from a fused ringwherein a ring corresponding to the above-mentioned 5- to 7-memberedmonocyclic aromatic heterocyclic group is fused with a C₆₋₁₄ aromatichydrocarbon; and a group derived from a fused ring wherein ringscorresponding to the above-mentioned 5- to 7-membered monocyclicaromatic heterocyclic groups are fused. Examples thereof includequinolyl (e.g., 2-quinolyl, 3-quinolyl, 4-quinolyl, 6-quinolyl),isoquinolyl (e.g., 3-isoquinolyl), quinazolyl (e.g., 2-quinazolyl,4-quinazolyl), quinoxalyl (e.g., 2-quinoxalyl, 6-quinoxalyl),benzofuranyl (e.g., 2-benzofuranyl, 3-benzofuranyl), benzothienyl (e.g.,2-benzothienyl, 3-benzothienyl), benzoxazolyl (e.g., 2-benzoxazolyl),benzisoxazolyl (e.g., 7-benzisoxazolyl), benzothiazolyl (e.g.,2-benzothiazolyl), benzimidazolyl (e.g., benzimidazol-1-yl,benzimidazol-2-yl, benzimidazol-5-yl), benzotriazolyl (e.g.,1H-1,2,3-benzotriazol-5-yl), indolyl (e.g., indol-1-yl, indol-2-yl,indol-3-yl, indol-5-yl), indazolyl (e.g., 1H-indazol-3-yl),pyrrolopyrazinyl (e.g., 1H-pyrrolo[2,3-b]pyrazin-2-yl,1H-pyrrolo[2,3-b]pyrazin-6-yl), imidazopyridyl (e.g.,1H-imidazo[4,5-b]pyridin-2-yl, 1H-imidazo[4,5-c]pyridin-2-yl,2H-imidazo[1,2-a]pyridin-3-yl), thienopyridyl (e.g.,thieno[2,3-b]pyridin-3-yl), imidazopyrazinyl (e.g.,1H-imidazo[4,5-b]pyrazin-2-yl), pyrazolopyridyl (e.g.,1H-pyrazolo[4,3-c]pyridin-3-yl), pyrazolothienyl (e.g.,2H-pyrazolo[3,4-b]thiophen-2-yl), pyrazolotriazinyl (e.g.,pyrazolo[5,1-c][1,2,4]triazin-3-yl) and the like.

In the present specification, the “non-aromatic heterocyclic group”means a monocyclic non-aromatic heterocyclic group or a fusednon-aromatic heterocyclic group, for example, a 3- to 12-memberednon-aromatic heterocyclic group, specifically a 3- to 8-memberedmonocyclic non-aromatic heterocyclic group or a 8- to 12-membered fusednon-aromatic heterocyclic group.

In the present specification, examples of the “monocyclic non-aromaticheterocyclic group” include a 3- to 8-membered (preferably 5- or6-membered) monocyclic non-aromatic heterocyclic group containing, as aring-constituting atom besides carbon atoms, 1 to 4 hetero atomsselected from an oxygen atom, a sulfur atom (optionally oxidized) and anitrogen atom (optionally oxidized). Examples thereof include azetidinyl(e.g., 1-azetidinyl, 2-azetidinyl), pyrrolidinyl (e.g., 1-pyrrolidinyl,2-pyrrolidinyl), piperidyl (e.g., piperidino, 2-piperidyl, 3-piperidyl,4-piperidyl), morpholinyl (e.g., morpholino), thiomorpholinyl (e.g.,thiomorpholino), piperazinyl (e.g., 1-piperazinyl, 2-piperazinyl,3-piperazinyl), oxazolidinyl (e.g., oxazolidin-2-yl), thiazolidinyl(e.g., thiazolidin-2-yl), dihydrothiopyranyl (e.g.,dihydrothiopyran-3-yl, dihydrothiopyran-4-yl), imidazolidinyl (e.g.,imidazolidin-2-yl, imidazolidin-3-yl), oxazolinyl (e.g., oxazolin-2-yl),thiazolinyl (e.g., thiazolin-2-yl), imidazolinyl (e.g., imidazolin-2-yl,imidazolin-3-yl), dioxolyl (e.g., 1,3-dioxol-4-yl), dioxolanyl (e.g.,1,3-dioxolan-4-yl), dihydrooxadiazolyl (e.g.,4,5-dihydro-1,2,4-oxadiazol-3-yl), pyranyl (e.g., 2-pyranyl, 4-pyranyl),tetrahydropyranyl (e.g., 2-tetrahydropyranyl, 3-tetrahydropyranyl,4-tetrahydropyranyl), thiopyranyl (e.g., 4-thiopyranyl),tetrahydrothiopyranyl (e.g., 2-tetrahydrothiopyranyl,3-tetrahydrothiopyranyl, 4-tetrahydrothiopyranyl),1-oxidotetrahydrothiopyranyl (e.g., 1-oxidotetrahydrothiopyran-4-yl),1,1-dioxidotetrahydrothiopyranyl (e.g.,1,1-dioxidotetrahydrothiopyran-4-yl), tetrahydrofuryl (e.g.,tetrahydrofuran-3-yl, tetrahydrofuran-2-yl), oxetanyl (e.g.,oxetan-2-yl, oxetan-3-yl), pyrazolidinyl (e.g., pyrazolidin-1-yl,pyrazolidin-3-yl), pyrazolinyl (e.g., pyrazolin-1-yl),tetrahydropyrimidinyl (e.g., tetrahydropyrimidin-1-yl), dihydrotriazolyl(e.g., 2,3-dihydro-1H-1,2,3-triazol-1-yl), tetrahydrothiazolyl (e.g.,2,3,4,5-tetrahydro-1H-1,2,3-triazol-1-yl), azepanyl (e.g., 1-azepanyl,2-azepanyl, 3-azepanyl, 4-azepanyl), dihydropyridyl (e.g.,dihydropyridin-1-yl, dihydropyridin-2-yl, dihydropyridin-3-yl,dihydropyridin-4-yl), tetrahydropyridyl (e.g.,1,2,3,4-tetrahydropyridin-1-yl, 1,2,3,4-tetrahydropyridin-2-yl,1,2,3,4-tetrahydropyridin-3-yl, 1,2,3,4-tetrahydropyridin-4-yl) and thelike.

In the present specification, examples of the “fused non-aromaticheterocyclic group” include an 8- to 12-membered fused non-aromaticheterocyclic group, specifically, a group derived from a fused ringwherein a ring corresponding to the above-mentioned 3- to 8-memberedmonocyclic non-aromatic heterocyclic group is fused with a C₆₋₁₄aromatic hydrocarbon; a group derived from a fused ring wherein ringscorresponding to the above-mentioned 3- to 8-membered monocyclicnon-aromatic heterocyclic groups are fused; a group derived from a fusedring wherein a ring corresponding to the above-mentioned 3- to8-membered monocyclic non-aromatic heterocyclic group is fused with aring corresponding to the above-mentioned 5- to 7-membered monocyclicaromatic heterocyclic group; and a group wherein the above-mentionedgroup is partially saturated. Examples thereof include dihydroindolyl(e.g., 2,3-dihydro-1H-indol-1-yl), dihydroisoindolyl (e.g.,1,3-dihydro-2H-isoindol-2-yl), dihydrobenzofuranyl (e.g.,2,3-dihydro-1-benzofuran-5-yl), tetrahydrobenzofuranyl (e.g.,4,5,6,7-tetrahydro-1-benzofuran-3-yl), dihydrobenzodioxinyl (e.g.,2,3-dihydro-1,4-benzodioxin-2-yl), dihydrobenzodioxepinyl (e.g.,3,4-dihydro-2H-1,5-benzodioxepin-2-yl), chromenyl (e.g.,4H-chromen-2-yl, 2H-chromen-3-yl), dihydrochromenyl (e.g.,3,4-dihydro-2H-chromen-2-yl), dihydroquinolyl (e.g.,1,2-dihydroquinolin-4-yl), tetrahydroquinolyl (e.g.,1,2,3,4-tetrahydroquinolin-4-yl), dihydroisoquinolyl (e.g.,1,2-dihydroisoquinolin-4-yl), tetrahydroisoquinolyl (e.g.,1,2,3,4-tetrahydroisoquinolin-4-yl), dihydrophthalazinyl (e.g.,1,4-dihydrophthalazin-4-yl) and the like.

The above-mentioned “monocyclic non-aromatic heterocyclic group” and“fused non-aromatic heterocyclic group” may be bridged, and examplesthereof include 3-oxa-6-azabicyclo[3.1.1]heptyl,8-oxa-3-azabicyclo[3.2.1]octyl, 2-oxa-5-azabicyclo[2.2.1]heptyl,3-oxa-8-azabicyclo[3.2.1]octyl, 6-oxa-3-azabicyclo[3.1.1]heptyl and thelike.

In the present specification, the “carbocyclic group” means a C₆₋₁₄ arylgroup, a C₃₋₁₀ cycloalkyl group, a C₃₋₁₀ cycloalkenyl group or a C₄₋₁₀cycloalkadienyl group. The “carbocyclic group” is optionally fused witha C₆₋₁₄ aromatic hydrocarbon, a C₃₋₁₀ cycloalkane, a C₃₋₁₀ cycloalkeneor a C₄₋₁₀ cycloalkadiene, or optionally form a spiro ring with a C₃₋₁₀cycloalkane, a C₃₋₁₀ cycloalkene or a C₄₋₁₀ cycloalkadiene, oroptionally bridged.

In the present specification, the “C₆₋₁₄ aromatic hydrocarbon” means,for example, benzene or naphthalene.

In the present specification, the “C₃₋₁₀ cycloalkane” means, forexample, cyclopropane, cyclobutane, cyclopentane, cyclohexane,cycloheptane, cyclooctane, cyclononane, cyclodecane or the like.

In the present specification, the “C₃₋₁₀ cycloalkene” means, forexample, cyclopropene, cyclobutene, cyclopentene, cyclohexene,cyclooctene, cyclononene, cyclodecene or the like.

In the present specification, the “C₄₋₁₀ cycloalkadiene” means, forexample, 1,3-cyclobutadiene, 1,3-cyclopentadiene, 1,4-cyclopentadiene,2,4-cyclopentadiene, 1,3-cyclohexadiene, 1,4-cyclohexadiene,1,5-cyclohexadiene, 2,4-cyclohexadiene, 2,5-cyclohexadiene,1,3-cyclooctadiene, 1,4-cyclooctadiene, 1,5-cyclooctadiene,1,6-cyclooctadiene, 1,7-cyclooctadiene, 2,4-cyclooctadiene,2,5-cyclooctadiene, 2,6-cyclooctadiene, 2,7-cyclooctadiene,3,5-cyclooctadiene, 3,6-cyclooctadiene or the like.

Each symbol of the formula (I) is explained below.

In the formula (I), R¹ is an optionally substituted C₁₋₆ alkyl group, anoptionally substituted hydroxy group, an optionally substituted aminogroup, an optionally substituted carbocyclic group, or an optionallysubstituted heterocyclic group, or R¹ is optionally bonded to the atomon Ring A to form, together with Ring A, a spiro ring or a fused ring,each of which is substituted by an oxo group and optionally furthersubstituted.

The “C₁₋₆ alkyl group” of the “optionally substituted C₁₋₆ alkyl group”for R¹ optionally has 1 to 5 (preferably 1 to 3) substituents atsubstitutable position(s). Examples of the substituent includesubstituents selected from the following Substituent Group A. When thenumber of the substituents is plural, the respective substituents may bethe same or different.

Substituent Group A:

(1) a halogen atom;(2) a cyano group;(3) a nitro group;(4) a hydroxy group;(5) a C₃₋₈ cycloalkyl group optionally substituted by 1 to 3substituents selected from

-   -   (a) a halogen atom,    -   (b) a cyano group,    -   (c) a C₁₋₆ alkyl group optionally substituted by 1 to 3 halogen        atoms, and    -   (d) a C₁₋₆ alkoxy group optionally substituted by 1 to 3 halogen        atoms;        (6) a C₆₋₁₄ aryl group optionally substituted by 1 to 3        substituents selected from    -   (a) a halogen atom,    -   (b) a cyano group,    -   (c) a C₁₋₆ alkyl group optionally substituted by 1 to 3 halogen        atoms, and    -   (d) a C₁₋₆ alkoxy group optionally substituted by 1 to 3 halogen        atoms;        (7) a C₁₋₆ alkoxy group optionally substituted by 1 to 3        substituents selected from    -   (a) a halogen atom,    -   (b) a cyano group,    -   (c) a C₃₋₈ cycloalkyl group optionally having 1 to 3 halogen        atoms,    -   (d) a C₃₋₈ cycloalkenyl group optionally having 1 to 3 halogen        atoms,    -   (e) a C₆₋₁₄ aryl group optionally having 1 to 3 halogen atoms,        and    -   (f) a 5- or 6-membered monocyclic aromatic heterocyclic group;        (8) a C₂₋₆ alkenyloxy group (e.g., vinyloxy, propenyloxy,        butenyloxy, pentenyloxy, hexenyloxy) optionally having 1 to 3        halogen atoms;        (9) a C₂₋₆ alkynyloxy group (e.g., ethynyloxy, propynyloxy,        butynyloxy, pentynyloxy, hexynyloxy) optionally having 1 to 3        halogen atoms;        (10) a C₃₋₈ cycloalkyloxy group (e.g., cyclopropyloxy,        cyclobutyloxy, cyclopentyloxy, cyclohexyloxy) optionally having        1 to 3 halogen atoms;        (11) a C₃₋₈ cycloalkenyloxy group (e.g., cyclopropenyloxy,        cyclobutenyloxy, cyclopentenyloxy, cyclohexenyloxy) optionally        having 1 to 3 halogen atoms;        (12) a C₆₋₁₄ aryloxy group optionally having 1 to 3 halogen        atoms;        (13) a C₇₋₁₄ aralkyloxy group optionally having 1 to 3 halogen        atoms;        (14) a carbamoyl group optionally mono- or di-substituted by        substituent(s) selected from    -   (a) a C₁₋₆ alkyl group,    -   (b) a C₃₋₆ cycloalkyl group,    -   (c) a C₆₋₁₄ aryl group,    -   (d) a C₁₋₆ alkoxy group,    -   (e) a 5- or 6-membered monocyclic aromatic heterocyclic group,    -   (f) an 8- to 12-membered fused aromatic heterocyclic group,    -   (g) a 3- to 8-membered monocyclic non-aromatic heterocyclic        group, and    -   (h) an 8- to 12-membered fused non-aromatic heterocyclic group;        (15) a sulfamoyl group optionally mono- or di-substituted by        substituent(s) selected from    -   (a) a C₁₋₆ alkyl group,    -   (b) a C₃₋₆ cycloalkyl group,    -   (c) a C₆₋₁₄ aryl group,    -   (d) a C₁₋₆ alkoxy group,    -   (e) a 5- or 6-membered monocyclic aromatic heterocyclic group,    -   (f) an 8- to 12-membered fused aromatic heterocyclic group,    -   (g) a 3- to 8-membered monocyclic non-aromatic heterocyclic        group, and    -   (h) an 8- to 12-membered fused non-aromatic heterocyclic group;        (16) a formyl group;        (17) a C₁₋₆ alkyl-carbonyl group;        (18) a C₂₋₆ alkenyl-carbonyl group (e.g., acryloyl, butenoyl,        pentenoyl, hexenoyl, heptenoyl);        (19) a C₂₋₆ alkynyl-carbonyl group (e.g., propioloyl,        propynylcarbonyl, butynylcarbonyl, pentynylcarbonyl,        hexynylcarbonyl);        (20) a C₃₋₈ cycloalkyl-carbonyl group (e.g.,        cyclopropylcarbonyl, cyclobutylcarbonyl, cyclopentylcarbonyl,        cyclohexylcarbonyl);        (21) a C₃₋₈ cycloalkenyl-carbonyl group (e.g.,        cyclopropenylcarbonyl, cyclobutenylcarbonyl,        cyclopentenylcarbonyl, cyclohexenylcarbonyl);        (22) a C₆₋₁₄ aryl-carbonyl group (e.g., benzoyl,        1-naphthylcarbonyl, 2-naphthylcarbonyl);        (23) a C₃₋₈ cycloalkyl-C₁₋₆ alkyl-carbonyl group (e.g.,        cyclopropylacetyl, 3-cyclopropylpropionyl, cyclobutylacetyl,        cyclopentylacetyl, cyclohexylacetyl, cyclohexylpropionyl);        (24) a C₃₋₈ cycloalkenyl-C₁₋₆ alkyl-carbonyl group (e.g.,        cyclopentenylacetyl, cyclohexenylacetyl,        3-cyclohexenylpropionyl, 3-cyclohexenylpropionyl);        (25) a C₇₋₁₄ aralkyl-carbonyl group (e.g., phenylacetyl,        3-phenylpropionyl);        (26) a 5- or 6-membered monocyclic aromatic heterocyclylcarbonyl        group (e.g., furylcarbonyl, thienylcarbonyl, pyrrolylcarbonyl,        oxazolylcarbonyl, isoxazolylcarbonyl, thiazolylcarbonyl,        isothiazolylcarbonyl, imidazolylcarbonyl, pyridylcarbonyl,        pyrazolylcarbonyl);        (27) an 8- to 12-membered fused aromatic heterocyclylcarbonyl        group (e.g., benzofuranylcarbonyl, isobenzofuranylcarbonyl,        benzothienylcarbonyl, isobenzothienylcarbonyl, indolylcarbonyl,        isoindolylcarbonyl, indazolylcarbonyl, benzimidazolylcarbonyl,        benzoxazolylcarbonyl);        (28) a 3- to 8-membered monocyclic non-aromatic        heterocyclylcarbonyl group (e.g., oxiranylcarbonyl,        azetidinylcarbonyl, oxetanylcarbonyl, thietanylcarbonyl,        pyrrolidinylcarbonyl, tetrahydrofurylcarbonyl,        thiolanylcarbonyl, piperidylcarbonyl);        (29) an 8- to 12-membered fused non-aromatic        heterocyclylcarbonyl group (e.g., dihydrobenzofuranyl);        (30) an amino group optionally mono- or di-substituted by        substituent(s) selected from    -   (a) a C₁₋₆ alkyl group optionally having 1 to 3 halogen atoms,    -   (b) a C₁₋₆ alkyl-carbonyl group optionally having 1 to 3 halogen        atoms,    -   (c) a C₃₋₈ cycloalkyl-carbonyl group,    -   (d) a C₆₋₁₄ aryl-carbonyl group optionally having 1 to 3 halogen        atoms,    -   (e) a 5- or 6-membered monocyclic aromatic heterocyclylcarbonyl        group,    -   (f) an 8- to 12-membered fused aromatic heterocyclylcarbonyl        group,    -   (g) a 3- to 8-membered monocyclic non-aromatic        heterocyclylcarbonyl group, and    -   (h) an 8- to 12-membered fused non-aromatic heterocyclylcarbonyl        group;        (31) a sulfanyl group;        (32) a C₁₋₆ alkylsulfanyl group (e.g., methylsulfanyl,        ethylsulfanyl);        (33) a C₂₋₆ alkenylsulfanyl group (e.g., vinylsulfanyl,        propenylsulfanyl);        (34) a C₂₋₆ alkynylsulfanyl group (e.g., ethynylsulfanyl,        propynylsulfanyl);        (35) a C₃₋₈ cycloalkylsulfanyl group (e.g., cyclopropylsulfanyl,        cyclobutylsulfanyl);        (36) a C₃₋₈ cycloalkenylsulfanyl group (e.g.,        cyclopropenylsulfanyl, cyclobutenylsulfanyl);        (37) a C₆₋₁₄ arylsulfanyl group (e.g., phenylsulfanyl);        (38) a C₃₋₈ cycloalkyl-C₁₋₆ alkylsulfanyl group (e.g.,        cyclopropylmethylsulfanyl);        (39) a C₃₋₈ cycloalkenyl-C₁₋₆ alkylsulfanyl group (e.g.,        cyclopentenylmethylsulfanyl);        (40) a C₁₋₆ alkylsulfinyl group (e.g., methylsulfinyl,        ethylsulfinyl);        (41) a C₂₋₆ alkenylsulfinyl group (e.g., vinylsulfinyl,        propenylsulfinyl);        (42) a C₂₋₆ alkynylsulfinyl group (e.g., ethynylsulfinyl,        propynylsulfinyl);        (43) a C₃₋₈ cycloalkylsulfinyl group (e.g., cyclopropylsulfinyl,        cyclobutylsulfinyl);        (44) a C₃₋₈ cycloalkenylsulfinyl group (e.g.,        cyclopropenylsulfinyl, cyclobutenylsulfinyl);        (45) a C₆₋₁₄ arylsulfinyl group (e.g., phenylsulfinyl);        (46) a C₃₋₈ cycloalkyl-C₁₋₆ alkylsulfinyl group (e.g.,        cyclopropylmethylsulfinyl);        (47) a C₃₋₈ cycloalkenyl-C₁₋₆ alkylsulfinyl group (e.g.,        cyclopentenylmethylsulfinyl);        (48) a C₁₋₆ alkylsulfonyl group (e.g., methylsulfonyl,        ethylsulfonyl);        (49) a C₂₋₆ alkenylsulfonyl group (e.g., vinylsulfonyl,        propenylsulfonyl);        (50) a C₂₋₆ alkynylsulfonyl group (e.g., ethynylsulfonyl,        propynylsulfonyl);        (51) a C₃₋₈ cycloalkylsulfonyl group (e.g., cyclopropylsulfonyl,        cyclobutylsulfonyl);        (52) a C₃₋₈ cycloalkenylsulfonyl group (e.g.,        cyclopropenylsulfonyl, cyclobutenylsulfonyl);        (53) a C₆₋₁₄ arylsulfonyl group (e.g., phenylsulfonyl);        (54) a C₃₋₈ cycloalkyl-C₁₋₆ alkylsulfonyl group (e.g.,        cyclopropylmethylsulfonyl);        (55) a C₃₋₈ cycloalkenyl-C₁₋₆ alkylsulfonyl group (e.g.,        cyclopentenylmethylsulfonyl);        (56) a C₆₋₁₄ aryl-C₁₋₆ alkylsulfonyl group (e.g.,        benzylsulfonyl);        (57) a 5- or 6-membered monocyclic aromatic heterocyclylsulfonyl        group (e.g., furylsulfonyl, thienylsulfonyl, pyridylsulfonyl);        (58) an 8- to 12-membered fused aromatic heterocyclylsulfonyl        group (e.g., benzofuranylsulfonyl, isobenzofuranylsulfonyl);        (59) a 3- to 8-membered monocyclic non-aromatic        heterocyclylsulfonyl group (e.g., oxiranylsulfonyl,        azetidinylsulfonyl);        (60) an 8- to 12-membered fused non-aromatic        heterocyclylsulfonyl group (e.g., dihydrobenzofuranylsulfonyl);        (61) a 5- or 6-membered monocyclic aromatic heterocyclic group        (e.g., furyl, thionyl, pyrrolyl, oxazolyl, isoxazolyl,        thiazolyl, isothiazolyl, imidazolyl, pyridyl, pyrazolyl,        morpholinyl) optionally substituted by 1 to 3 substituents        selected from    -   (a) a halogen atom,    -   (b) a C₁₋₆ alkyl group optionally substituted by 1 to 3 halogen        atoms, and    -   (c) a C₁₋₆ alkoxy group optionally substituted by 1 to 3 halogen        atoms;        (62) an 8- to 12-membered fused aromatic heterocyclic group        (e.g., benzofuranyl, isobenzofuranyl, benzothienyl,        isobenzothienyl, indolyl, isoindolyl, indazolyl, benzimidazolyl,        benzoxazolyl) optionally substituted by 1 to 3 substituents        selected from    -   (a) a halogen atom,    -   (b) a C₁₋₆ alkyl group optionally substituted by 1 to 3 halogen        atoms, and    -   (c) a C₁₋₆ alkoxy group optionally substituted by 1 to 3 halogen        atoms;        (63) a 3- to 8-membered monocyclic non-aromatic heterocyclic        group (e.g., oxiranyl, azetidinyl, oxetanyl, thietanyl,        pyrrolidinyl, tetrahydrofuryl, thiolanyl, piperidyl,        piperazinyl, dihydrooxadiazolyl, thiazolinyl) optionally        substituted by 1 to 3 substituents selected from    -   (a) a halogen atom,    -   (b) a C₁₋₆ alkyl group optionally substituted by 1 to 3 halogen        atoms,    -   (c) a C₁₋₆ alkoxy group optionally substituted by 1 to 3 halogen        atoms, and    -   (d) an oxo group;        (64) an 8- to 12-membered fused non-aromatic heterocyclic group        (e.g., dihydrobenzofuranyl) optionally substituted by 1 to 3        substituents selected from    -   (a) a halogen atom,    -   (b) a C₁₋₆ alkyl group optionally substituted by 1 to 3 halogen        atoms,    -   (c) a C₁₋₆ alkoxy group optionally substituted by 1 to 3 halogen        atoms, and    -   (d) an oxo group;        (65) a 5- or 6-membered monocyclic aromatic heterocyclyloxy        group (e.g., furyloxy, thienyloxy, pyrrolyloxy, oxazolyloxy,        isoxazolyloxy, thiazolyloxy, isothiazolyloxy, imidazolyloxy,        pyridyloxy, pyrazolyloxy);        (66) an 8- to 12-membered fused aromatic heterocyclyloxy group        (e.g., benzofuranyloxy, isobenzofuranyloxy, benzothienyloxy,        isobenzothienyloxy, indolyloxy, isoindolyloxy, indazolyloxy,        benzimidazolyloxy, benzoxazolyloxy);        (67) a 3- to 8-membered monocyclic non-aromatic heterocyclyloxy        group (e.g., oxiranyloxy, azetidinyloxy, oxetanyloxy,        thietanyloxy, pyrrolidinyloxy, tetrahydrofuryloxy, thiolanyloxy,        piperidyloxy);        (68) an 8- to 12-membered fused non-aromatic heterocyclyloxy        group (e.g., dihydrobenzofuranyloxy);        (69) a carboxy group;        (70) a C₁₋₆ alkoxy-carbonyl group;        (71) a C₂₋₆ alkenyloxy-carbonyl group (e.g., vinyloxycarbonyl,        propenyloxycarbonyl, butenyloxycarbonyl, pentenyloxycarbonyl,        hexenyloxycarbonyl);        (72) a C₂₋₆ alkynyloxy-carbonyl group (e.g., ethynyloxycarbonyl,        propynyloxycarbonyl, butynyloxycarbonyl, pentynyloxycarbonyl,        hexynyloxycarbonyl);        (73) a C₃₋₈ cycloalkyloxy-carbonyl group (e.g.,        cyclopropyloxycarbonyl, cyclobutyloxycarbonyl,        cyclopentyloxycarbonyl, cyclohexyloxycarbonyl);        (74) a C₃₋₈ cycloalkenyloxy-carbonyl group (e.g.,        cyclopropenyloxycarbonyl, cyclobutenyloxycarbonyl,        cyclopentenyloxycarbonyl, cyclohexenyloxycarbonyl);        (75) a C₆₋₁₄ aryloxy-carbonyl group (e.g., phenoxycarbonyl,        1-naphthyloxycarbonyl, 2-naphthyloxycarbonyl);        (76) a C₃₋₈ cycloalkyl-C₁₋₆ alkoxy-carbonyl group (e.g.,        cyclopropylmethyloxycarbonyl, cyclopropylethyloxycarbonyl,        cyclobutylmethyloxycarbonyl, cyclopentylmethyloxycarbonyl,        cyclohexylmethyloxycarbonyl, cyclohexylethyloxycarbonyl);        (77) a C₃₋₈ cycloalkenyl-C₁₋₆ alkoxy-carbonyl group (e.g.,        cyclopentenylmethyloxycarbonyl, cyclohexenylmethyloxycarbonyl,        cyclohexenylethyloxycarbonyl, cyclohexenylpropyloxycarbonyl);        (78) a C₇₋₁₄ aralkyloxy-carbonyl group (e.g., benzyloxycarbonyl,        phenethyloxycarbonyl);        (79) a mono-C₁₋₆ alkylthiocarbamoyl group (e.g.,        methylthiocarbamoyl, ethylthiocarbamoyl, propylthiocarbamoyl);        (80) a di-C₁₋₆ alkylthiocarbamoyl group (e.g.,        dimethylthiocarbamoyl, diethylthiocarbamoyl,        dipropylthiocarbamoyl);        (81) a C₁₋₆ alkyl-carbonyloxy group (e.g., acetyloxy,        propanoyloxy, butanoyloxy, 2-methylpropanoyloxy);        (82) an imino group optionally substituted by a hydroxy group;        and        (83) a C₁₋₆ alkylenedioxy group (e.g., methylenedioxy,        ethylenedioxy).

Examples of the “optionally substituted hydroxy group” for R¹ include ahydroxy group optionally substituted by a substituent selected from aC₁₋₁₀ alkyl group, a C₂₋₁₀ alkenyl group, a C₃₋₁₀ cycloalkyl group, aC₃₋₁₀ cycloalkenyl group, a C₆₋₁₄ aryl group, a C₇₋₁₄ aralkyl group, aC₈₋₁₃ arylalkenyl group, a C₁₋₆ alkyl-carbonyl group, a heterocyclicgroup (e.g., an aromatic heterocyclic group, a non-aromatic heterocyclicgroup) and the like, each of which is optionally substituted.

The C₁₋₁₀ alkyl group, C₂₋₁₀ alkenyl group and C₁₋₆ alkyl-carbonyl groupoptionally have 1 to 5 (preferably 1 to 3) substituents at substitutableposition(s). Examples of the substituent include substituents selectedfrom the above-mentioned Substituent Group A. When the number of thesubstituents is plural, the respective substituents may be the same ordifferent.

The C₃₋₁₀ cycloalkyl group, C₃₋₁₀ cycloalkenyl group and non-aromaticheterocyclic group optionally have 1 to 5 (preferably 1 to 3)substituents at substitutable position(s). Examples of the substituentinclude substituents selected from the following Substituent Group B.When the number of the substituents is plural, the respectivesubstituents may be the same or different.

Substituent Group B:

(1) the above-mentioned Substituent Group A;(2) a C₁₋₆ alkyl group optionally substituted by 1 to 3 substituentsselected from

-   -   (a) a halogen atom,    -   (b) a cyano group,    -   (c) a hydroxy group,    -   (d) a C₃₋₈ cycloalkyl group optionally substituted by 1 to 3        substituents selected from        -   (i) a halogen atom,        -   (ii) a cyano group, and        -   (iii) a C₁₋₆ alkyl group optionally substituted by 1 to 3            halogen atoms;    -   (e) a C₆₋₁₄ aryl group optionally substituted by 1 to 3        substituents selected from        -   (i) a halogen atom,        -   (ii) a cyano group, and        -   (iii) a C₁₋₆ alkyl group optionally substituted by 1 to 3            halogen atoms,    -   (f) a C₁₋₆ alkoxy group optionally substituted by 1 to 3 halogen        atoms,    -   (g) an amino group optionally mono- or di-substituted by C₁₋₆        alkyl group(s),    -   (h) a 5- or 6-membered monocyclic aromatic heterocyclic group,    -   (i) a 8- to 12-membered fused aromatic heterocyclic group,    -   (j) a 3- to 8-membered monocyclic non-aromatic heterocyclic        group,    -   (k) a 8- to 12-membered fused non-aromatic heterocyclic group,    -   (l) a carboxy group, and    -   (m) a C₁₋₆ alkoxy-carbonyl group optionally substituted by 1 to        3 halogen atoms;        (3) a C₂₋₆ alkenyl group optionally substituted by 1 to 3        substituents selected from    -   (a) a halogen atom,    -   (b) a hydroxy group,    -   (c) a C₁₋₆ alkoxy group,    -   (d) an amino group optionally mono- or di-substituted by C₁₋₆        alkyl group(s),    -   (e) a carboxy group, and    -   (f) a C₁₋₆ alkoxy-carbonyl group;        (4) a C₇₋₁₄ aralkyl group optionally substituted by 1 to 3        substituents selected from    -   (a) a halogen atom,    -   (b) a hydroxy group,    -   (c) a C₁₋₆ alkoxy group, and    -   (d) a C₁₋₆ alkyl group optionally substituted by 1 to 3 halogen        atoms; and        (5) an oxo group.

The C₆₋₁₄ aryl group, C₇₋₁₄ aralkyl group, C₈₋₁₃ arylalkenyl group andaromatic heterocyclic group have 1 to 5 (preferably 1 to 3) substituentsat substitutable position(s). Examples of the substituent includesubstituents selected from the above-mentioned Substituent Group Bexcluding oxo. When the number of the substituents is plural, therespective substituents may be the same or different.

Examples of the “amino group” of the “optionally substituted aminogroup” for R¹ include an amino group optionally mono- or di-substitutedby substituent(s) selected from a C₁₋₁₀ alkyl group, a C₂₋₁₀ alkenylgroup, a C₃₋₁₀ cycloalkyl group, a C₃₋₁₀ cycloalkenyl group, a C₆₋₁₄aryl group, a C₇₋₁₄ aralkyl group, a C₈₋₁₃ arylalkenyl group, aheterocyclic group (e.g., an aromatic heterocyclic group, a non-aromaticheterocyclic group) and the like, each of which is optionallysubstituted; and an acyl group. When the amino group is di-substituted,the two substituent in combination optionally form an optionallysubstituted heterocyclic group.

The C₁₋₁₀ alkyl group and C₂₋₁₀ alkenyl group optionally have 1 to 5(preferably 1 to 3) substituents at substitutable position(s). Examplesof the substituent include substituents selected from theabove-mentioned Substituent Group A. When the number of the substituentsis plural, the respective substituents may be the same or different.

The C₃₋₁₀ cycloalkyl group, C₃₋₁₀ cycloalkenyl group and non-aromaticheterocyclic group optionally have 1 to 5 (preferably 1 to 3)substituents at substitutable position(s). Examples of the substituentinclude substituents selected from the above-mentioned Substituent GroupB. When the number of the substituents is plural, the respectivesubstituents may be the same or different.

The C₆₋₁₄ aryl group, C₇₋₁₄ aralkyl group, C₈₋₁₃ arylalkenyl group andaromatic heterocyclic group optionally have 1 to 5 (preferably 1 to 3)substituents at substitutable position(s). Examples of the substituentinclude substituents selected from the above-mentioned Substituent GroupB excluding oxo. When the number of the substituents is plural, therespective substituents may be the same or different.

Examples of the “acyl group” exemplified as the substituent for the“amino group” include a group represented by the formula: —COR^(A),—CO—OR^(A), —SO₃R^(A), —S(O)₂R^(A), —SOR^(A), —CO—NR^(A)′R^(B)′,—CS—NR^(A)′R^(B)′ or —S(O)₂NR^(A)′R^(B)′ wherein R^(A) is a hydrogenatom, an optionally substituted hydrocarbon group, or an optionallysubstituted heterocyclic group, and R^(A)′ and R^(B)′ are the same ordifferent and each is a hydrogen atom, an optionally substitutedhydrocarbon group, or an optionally substituted heterocyclic group, orR^(A)′ and R^(B)′ in combination optionally form, together with theadjacent nitrogen atom, an optionally substituted nitrogen-containingheterocyclic, and the like.

Examples of the “hydrocarbon group” of the “optionally substitutedhydrocarbon group” for R^(A), R^(A)′ or R^(B)′ include a C₁₋₁₀ alkylgroup, a C₂₋₁₀ alkenyl group, a C₂₋₁₀ alkynyl group, a C₃₋₁₀ cycloalkylgroup, a C₃₋₁₀ cycloalkenyl group, a C₄₋₁₀ cycloalkadienyl group, aC₆₋₁₄ aryl group, a C₇₋₁₄ aralkyl group, a C₈₋₁₃ arylalkenyl group andthe like.

The C₁₋₁₀ alkyl group, C₂₋₁₀ alkenyl group and C₂₋₁₀ alkynyl group,which are exemplified as the above-mentioned “hydrocarbon group”,optionally have 1 to 5 (preferably 1 to 3) substituents at substitutableposition(s). Examples of the substituent include substituents selectedfrom the above-mentioned Substituent Group A. When the number of thesubstituents is plural, the respective substituents may be the same ordifferent.

The C₃₋₁₀ cycloalkyl group, C₃₋₁₀ cycloalkenyl group and C₄₋₁₀cycloalkadienyl group, which are exemplified as the above-mentioned“hydrocarbon group”, optionally have 1 to 5 (preferably 1 to 3)substituents at substitutable position(s). Examples of the substituentinclude substituents selected from the above-mentioned Substituent GroupB. When the number of the substituents is plural, the respectivesubstituents may be the same or different.

The C₆₋₁₄ aryl group, C₇₋₁₄ aralkyl group and C₈₋₁₃ arylalkenyl group,which are exemplified as the above-mentioned “hydrocarbon group”,optionally have 1 to 5 (preferably 1 to 3) substituents at substitutableposition(s). Examples of the substituent include substituents selectedfrom the above-mentioned Substituent Group B excluding an oxo group.When the number of the substituents is plural, the respectivesubstituents may be the same or different.

The “heterocyclic group” of the “optionally substituted heterocyclicgroup” for R^(A), R^(A)′ or R^(B)′ optionally has 1 to 5 (preferably 1to 3) substituents at substitutable position(s). Examples of thesubstituent for the aromatic heterocyclic group include theabove-mentioned Substituent Group B excluding an oxo group, and examplesof the substituent for the non-aromatic heterocyclic group include theabove-mentioned Substituent Group B. When the number of the substituentsis plural, the respective substituents may be the same or different.

Examples of the “nitrogen-containing heterocycle” of the “optionallysubstituted nitrogen-containing heterocycle” formed by R^(A)′ and R^(B)′together with the adjacent nitrogen atom include a 5- to 7-memberednitrogen-containing heterocycle containing, as a ring-constituting atombesides carbon atoms, at least one nitrogen atom and optionally furthercontaining one or two hetero atoms selected from an oxygen atom, asulfur atom and a nitrogen atom. Preferable examples of thenitrogen-containing heterocycle include pyrrolidine, imidazolidine,pyrazolidine, piperidine, piperazine, morpholine, thiomorpholine and thelike.

The nitrogen-containing heterocycle optionally has 1 to 5 (preferably 1to 3) substituents at substitutable position(s). Examples of thesubstituent include substituents selected from the above-mentionedSubstituent Group B. When the number of the substituents is plural, therespective substituents may be the same or different.

Preferable examples of the “acyl group” include

(1) a formyl group;(2) a carboxy group;(3) a C₁₋₆ alkyl-carbonyl group (e.g., acetyl) optionally substituted by1 to 3 halogen atoms;(4) a C₁₋₆ alkoxy-carbonyl group (e.g., methoxycarbonyl, ethoxycarbonyl,propoxycarbonyl, tert-butoxycarbonyl) optionally substituted by 1 to 3halogen atoms;(5) a C₃₋₁₀ cycloalkyl-carbonyl group (e.g., cyclopropylcarbonyl,cyclopentylcarbonyl, cyclohexylcarbonyl);(6) a C₆₋₁₄ aryl-carbonyl group (e.g., benzoyl, 1-naphthoyl,2-naphthoyl) optionally substituted by 1 to 3 halogen atoms;(7) a carbamoyl group optionally mono- or di-substituted bysubstituent(s) selected from

-   -   (a) a C₁₋₆ alkyl group optionally substituted by 1 to 3        substituents selected from a halogen atom, a C₁₋₆ alkoxy group,        a C₁₋₆ alkoxy-carbonyl group and a carboxy group, and    -   (b) an amino group optionally mono- or di-substituted by C₁₋₆        alkoxy-carbonyl group(s);        (8) a C₁₋₆ alkylsulfonyl group (e.g., methylsulfonyl,        ethylsulfonyl, isopropylsulfonyl) optionally substituted by 1 to        3 halogen atoms;        (9) a C₆₋₁₄ arylsulfonyl group (e.g., benzenesulfonyl);        (10) a sulfamoyl group;        (11) a thiocarbamoyl group;        (12) an aromatic heterocyclylcarbonyl group (e.g.,        furylcarbonyl, thienylcarbonyl) optionally substituted by 1 to 3        substituents selected from a C₁₋₆ alkyl group optionally        substituted by 1 to 3 halogen atoms;        (13) a non-aromatic heterocyclylcarbonyl group (e.g.,        tetrahydrofurylcarbonyl, pyrrolidinylcarbonyl) optionally        substituted by 1 to 3 substituents selected from a C₁₋₆ alkyl        group optionally substituted by 1 to 3 halogen atoms; and the        like.

The “carbocyclic group” of the “optionally substituted carbocyclicgroup” for R¹ optionally has 1 to 5 (preferably 1 to 3) substituents atsubstitutable position(s). Examples of the substituent for the C₆₋₁₄aryl group include the above-mentioned Substituent Group B excluding anoxo group, and examples of the substituent for the C₃₋₁₀ cycloalkylgroup, C₃₋₁₀ cycloalkenyl group and C₄₋₁₀ cycloalkadienyl group includethe above-mentioned Substituent Group B. When the number of thesubstituents is plural, the respective substituents may be the same ordifferent.

The “heterocyclic group” of the “optionally substituted heterocyclicgroup” for R¹ optionally has 1 to 5 (preferably 1 to 3) substituents atsubstitutable position(s). Examples of the substituent for the aromaticheterocyclic group include the above-mentioned Substituent Group Bexcluding an oxo group, and examples of the substituent for thenon-aromatic heterocyclic group include the above-mentioned SubstituentGroup B. When the number of the substituents is plural, the respectivesubstituents may be the same or different.

Examples of the “spiro ring or fused ring, each of which is substitutedby an oxo group and optionally further substituted” formed by R¹ and theatom on Ring A in combination, together with Ring A, include spiro ringssuch as 2,8-diazaspiro[4.5]decane, 2,7-diazaspiro[3.5]nonane and thelike, and fused rings such as hexahydroimidazo[1,5-a]pyrazine,hexahydropyrrolo[1,2-a]pyrazine and the like.

The “spiro ring or fused ring” of the “spiro ring or fused ring, each ofwhich is substituted by an oxo group and optionally further substituted”formed by R¹ and the atom on Ring A in combination, together with RingA, optionally has 1 to 5 (preferably 1 to 3) substituents atsubstitutable position(s). Examples of the substituent includesubstituents selected from the above-mentioned Substituent Group B. Whenthe number of the substituents is plural, the respective substituentsmay be the same or different.

R¹ is preferably an optionally substituted C₁₋₆ alkyl group, anoptionally substituted C₁₋₆ alkoxy group, an optionally substitutedamino group, an optionally substituted C₃₋₈ cycloalkyl group, anoptionally substituted C₆₋₁₄ aryl group, or an optionally substitutednon-aromatic heterocyclic group, or R¹ is bonded to the atom on Ring Ato form, together with Ring A, a spiro ring substituted by oxo andoptionally further substituted.

R¹ is more preferably

(1) a C₁₋₆ alkyl group (e.g., methyl, ethyl) optionally substituted by 1to 3 substituents selected from

-   -   (a) a cyano group,    -   (b) a C₆₋₁₄ aryl group (e.g., phenyl) optionally substituted by        1 to 3 C₁₋₆ alkoxy groups (e.g., methoxy),    -   (c) a C₆₋₁₄ aryloxy group (e.g., phenoxy),    -   (d) a C₃₋₈ cycloalkyl group (e.g., cyclopropyl),    -   (e) a 5- or 6-membered monocyclic aromatic heterocyclic group        (e.g., pyrazolyl),    -   (f) a 8- to 12-membered fused aromatic heterocyclic group (e.g.,        indazolyl), and    -   (g) a 3- to 8-membered monocyclic non-aromatic heterocyclic        group (e.g., dihydropyridyl) optionally substituted by 1 to 3        oxo groups,        (2) a C₁₋₆ alkoxy group (e.g., methoxy, tert-butoxy, preferably        a C₁₋₃ alkoxy group (e.g., methoxy)) optionally substituted by 1        to 3 C₆₋₁₄ aryl groups (e.g., phenyl),        (3) an amino group optionally mono- or di-substituted by        substituent(s) selected from    -   (a) a C₁₋₆ alkyl group (e.g., methyl, ethyl) optionally        substituted by 1 to 3 substituents selected from        -   (i) a halogen atom (e.g., a fluorine atom),        -   (ii) a cyano group,        -   (iii) a C₃₋₈ cycloalkyl group (e.g., cyclopropyl,            cyclobutyl),        -   (iv) a C₆₋₁₄ aryl group (e.g., phenyl) optionally            substituted by 1 to 3 halogen atoms (e.g., a fluorine atom),        -   (v) a 5- or 6-membered monocyclic aromatic heterocyclic            group (e.g., pyridyl), and        -   (vi) a 3- to 8-membered monocyclic non-aromatic heterocyclic            group (e.g., oxetanyl) optionally substituted by 1 to 3 C₁₋₆            alkyl groups (e.g., methyl),    -   (b) a C₃₋₈ cycloalkyl group (e.g., cyclopropyl, cyclobutyl,        cyclopentyl) optionally substituted by 1 to 3 halogen atoms        (e.g., a fluorine atom),    -   (c) a C₆₋₁₄ aryl group (e.g., phenyl), and    -   (d) a 3- to 8-membered monocyclic non-aromatic heterocyclic        group (e.g., tetrahydropyranyl, oxetanyl, tetrahydrofuryl,        pyrrolidinyl) optionally substituted by 1 to 3 C₁₋₆ alkyl groups        (e.g., methyl),        (4) a C₃₋₈ cycloalkyl group (e.g., cyclopropyl) optionally        substituted by 1 to 3 C₆₋₁₄ aryl groups (e.g., phenyl),        (5) a C₆₋₁₄ aryl group (e.g., phenyl), or        (6) a 3- to 12-membered non-aromatic heterocyclic group        (preferably a 3- to 8-membered monocyclic non-aromatic        heterocyclic group (e.g., azetidinyl, pyrrolidinyl, piperidyl,        piperazinyl, morpholinyl, 1,1-dioxidothiomorpholinyl,        tetrahydropyranyl, 3-oxa-6-azabicyclo[3.1.1]heptyl,        8-oxa-3-azabicyclo[3.2.1]octyl, 2-oxa-5-azabicyclo[2.2.1]heptyl,        3-oxa-8-azabicyclo[3.2.1]octyl,        6-oxa-3-azabicyclo[3.1.1]heptyl)) optionally substituted by 1 to        5 substituents selected from    -   (a) a halogen atom (e.g., a fluorine atom),    -   (b) a cyano group,    -   (c) a hydroxy group,    -   (d) an oxo group,    -   (e) a carbamoyl group,    -   (f) a C₁₋₆ alkyl group (e.g., methyl, ethyl, isopropyl)        optionally substituted by 1 to 3 substituents selected from        -   (i) a hydroxy group, and        -   (ii) a C₁₋₆ alkoxy group (e.g., methoxy),    -   (g) a C₁₋₆ alkoxy group (e.g., methoxy, ethoxy, isopropoxy),    -   (h) a C₁₋₆ alkoxy-carbonyl group (e.g., methoxycarbonyl), and    -   (i) a C₆₋₁₄ aryl group (e.g., phenyl) optionally substituted by        1 to 3 halogen atoms (e.g., a fluorine atom), or        R¹ is bonded to the atom on Ring A to form, together with Ring        A, a spiro ring (e.g., 2,8-diazaspiro[4.5]decane) substituted by        oxo and optionally further substituted by 1 to 3 C₁₋₆ alkyl        groups (e.g., methyl).

In another embodiment, R¹ is more preferably

(1) a C₁₋₆ alkyl group (e.g., methyl, ethyl) optionally substituted by 1to 3 substituents selected from

-   -   (a) a cyano group,    -   (b) a C₆₋₁₄ aryl group (e.g., phenyl) optionally substituted by        1 to 3 C₁₋₆ alkoxy groups (e.g., methoxy),    -   (c) a C₆₋₁₄ aryloxy group (e.g., phenoxy),    -   (d) a C₃₋₈ cycloalkyl group (e.g., cyclopropyl),    -   (e) a 5- or 6-membered monocyclic aromatic heterocyclic group        (e.g., pyrazolyl),    -   (f) a 8- to 12-membered fused aromatic heterocyclic group (e.g.,        indazolyl), and    -   (g) a 3- to 8-membered monocyclic non-aromatic heterocyclic        group (e.g., dihydropyridyl) optionally substituted by 1 to 3        oxo groups,        (2) a C₁₋₆ alkoxy group (e.g., methoxy, tert-butoxy, preferably        a C₁₋₃ alkoxy group (e.g., methoxy)) optionally substituted by 1        to 3 C₆₋₁₄ aryl groups (e.g., phenyl),        (3) an amino group optionally mono- or di-substituted by        substituent(s) selected from    -   (a) a C₁₋₆ alkyl group (e.g., methyl, ethyl) optionally        substituted by 1 to 3 substituents selected from        -   (i) a halogen atom (e.g., a fluorine atom),        -   (ii) a cyano group,        -   (iii) a C₃₋₈ cycloalkyl group (e.g., cyclopropyl,            cyclobutyl),        -   (iv) a C₆₋₁₄ aryl group (e.g., phenyl) optionally so            substituted by 1 to 3 substituents selected from a halogen            atom (e.g., a fluorine atom) and a C₁₋₆ alkoxy group (e.g.,            methoxy),        -   (v) a 5- or 6-membered monocyclic aromatic heterocyclic            group (e.g., pyridyl), and        -   (vi) a 3- to 8-membered monocyclic non-aromatic heterocyclic            group (e.g., oxetanyl) optionally substituted by 1 to 3 C₁₋₆            alkyl groups (e.g., methyl),    -   (b) a C₃₋₈ cycloalkyl group (e.g., cyclopropyl, cyclobutyl,        cyclopentyl) optionally substituted by 1 to 3 halogen atoms        (e.g., a fluorine atom),    -   (c) a C₆₋₁₄ aryl group (e.g., phenyl), and    -   (d) a 3- to 8-membered monocyclic non-aromatic heterocyclic        group (e.g., tetrahydropyranyl, oxetanyl, tetrahydrofuryl,        pyrrolidinyl) optionally substituted by 1 to 3 C₁₋₆ alkyl groups        (e.g., methyl),        (4) a C₃₋₈ cycloalkyl group (e.g., cyclopropyl) optionally        substituted by 1 to 3 C₆₋₁₄ aryl groups (e.g., phenyl),        (5) a C₆₋₁₄ aryl group (e.g., phenyl), or        (6) a 3- to 12-membered non-aromatic heterocyclic group        (preferably a 3- to 8-membered monocyclic non-aromatic        heterocyclic group (e.g., azetidinyl, pyrrolidinyl, piperidyl,        piperazinyl, morpholinyl, 1,1-dioxidothiomorpholinyl,        tetrahydropyranyl, 3-oxa-6-azabicyclo[3.1.1]heptyl,        8-oxa-3-azabicyclo[3.2.1]octyl, 2-oxa-5-azabicyclo[2.2.1]heptyl,        3-oxa-8-azabicyclo[3.2.1]octyl,        6-oxa-3-azabicyclo[3.1.1]heptyl),        3,7-dioxa-9-azabicyclo[3.3.1]nonyl)) optionally substituted by 1        to 5 substituents selected from    -   (a) a halogen atom (e.g., a fluorine atom),    -   (b) a cyano group,    -   (c) a hydroxy group,    -   (d) an oxo group,    -   (e) a carbamoyl group optionally mono- or di-substituted by C₁₋₆        alkyl group(s) (e.g., methyl),    -   (f) a C₁₋₆ alkyl group (e.g., methyl, ethyl, isopropyl)        optionally substituted by 1 to 3 substituents selected from        -   (i) a hydroxy group, and        -   (ii) a C₁₋₆ alkoxy group (e.g., methoxy),    -   (g) a C₁₋₆ alkoxy group (e.g., methoxy, ethoxy, isopropoxy)        optionally substituted by 1 to 3 halogen atoms (e.g., a fluorine        atom),    -   (h) a C₁₋₆ alkoxy-carbonyl group (e.g., methoxycarbonyl), and    -   (i) a C₆₋₁₄ aryl group (e.g., phenyl) optionally substituted by        1 to 3 halogen atoms (e.g., a fluorine atom), or        R¹ is bonded to the atom on Ring A to form, together with Ring        A, a spiro ring (e.g., 2,8-diazaspiro[4.5]decane) substituted by        oxo and optionally further substituted by 1 to 3 C₁₋₆ alkyl        groups (e.g., methyl).

R¹ is still more preferably

(1) a C₁₋₆ alkyl group (e.g., methyl, ethyl) optionally substituted by 1to 3 substituents selected from

-   -   (a) a C₃₋₈ cycloalkyl group (e.g., cyclopropyl), and    -   (b) a 8- to 12-membered fused aromatic heterocyclic group (e.g.,        indazolyl),        (2) a C₁₋₆ alkoxy group (preferably a C₁₋₃ alkoxy group (e.g.,        methoxy)) optionally substituted by 1 to 3 C₆₋₁₄ aryl groups        (e.g., phenyl),        (3) an amino group optionally mono- or di-substituted by        substituent(s) selected from    -   (a) a C₁₋₆ alkyl group (e.g., methyl, ethyl) optionally        substituted by 1 to 3 substituents selected from        -   (i) a halogen atom (e.g., a fluorine atom),        -   (ii) a C₆₋₁₄ aryl group (e.g., phenyl) optionally            substituted by 1 to 3 halogen atoms (e.g., a fluorine atom),        -   (iii) a 5- or 6-membered monocyclic aromatic heterocyclic            group (e.g., pyridyl), and        -   (iv) a 3- to 8-membered monocyclic non-aromatic heterocyclic            group (e.g., oxetanyl) optionally substituted by 1 to 3 C₁₋₆            alkyl groups (e.g., methyl),    -   (b) a C₃₋₈ cycloalkyl group (e.g., cyclopropyl, cyclopentyl),    -   (c) a 3- to 8-membered monocyclic non-aromatic heterocyclic        group (e.g., tetrahydropyranyl, tetrahydrofuryl), and    -   (d) a C₆₋₁₄ aryl group (e.g., phenyl),        (4) a C₃₋₈ cycloalkyl group (e.g., cyclopropyl), or        (5) a 3- to 8-membered monocyclic non-aromatic heterocyclic        group (e.g., azetidinyl, pyrrolidinyl,        1,1-dioxidothiomorpholinyl, 3-oxa-6-azabicyclo[3.1.1]heptyl)        optionally substituted by 1 to 5 substituents selected from    -   (a) a halogen atom (e.g., a fluorine atom),    -   (b) a cyano group,    -   (c) a carbamoyl group,    -   (d) a C₁₋₆ alkyl group (e.g., methyl, isopropyl) optionally        substituted by 1 to 3 C₁₋₆ alkoxy groups (e.g., methoxy),    -   (e) a C₁₋₆ alkoxy group (e.g., methoxy), and    -   (f) a C₆₋₁₄ aryl group (e.g., phenyl) optionally substituted by        1 to 3 halogen atoms (e.g., a fluorine atom), or        R¹ is bonded to the atom on Ring A to form, together with Ring        A, a spiro ring (e.g., 2,8-diazaspiro[4.5]decane) substituted by        oxo and optionally further substituted by 1 to 3 C₁₋₁₆ alkyl        groups (e.g., methyl).

In another embodiment, R¹ is preferably an optionally substituted C₁₋₆alkyl group, an optionally substituted C₁₋₆ alkoxy group, an optionallysubstituted amino group, an optionally substituted C₃₋₈ cycloalkylgroup, an optionally substituted C₆₋₁₄ aryl group, or an optionallysubstituted non-aromatic heterocyclic group.

R¹ is more preferably

(1) a C₁₋₆ alkyl group (e.g., methyl, ethyl) optionally substituted by 1to 3 substituents selected from

-   -   (a) a cyano group,    -   (b) a C₆₋₁₄ aryl group (e.g., phenyl) optionally substituted by        1 to 3 C₁₋₆ alkoxy groups (e.g., methoxy),    -   (c) a C₆₋₁₄ aryloxy group (e.g., phenoxy),    -   (d) a C₃₋₆ cycloalkyl group (e.g., cyclopropyl),    -   (e) a 5- or 6-membered monocyclic aromatic heterocyclic group        (e.g., pyrazolyl),    -   (f) a 8- to 12-membered fused aromatic heterocyclic group (e.g.,        indazolyl), and    -   (g) a 3- to 8-membered monocyclic non-aromatic heterocyclic        group (e.g., dihydropyridyl) optionally substituted by 1 to 3        oxo groups,        (2) a C₁₋₆ alkoxy group (e.g., methoxy, tert-butoxy, preferably        a C₁₋₃ alkoxy group (e.g., methoxy)) optionally substituted by 1        to 3 C₆₋₁₄ aryl groups (e.g., phenyl),        (3) an amino group optionally mono- or di-substituted by        substituent(s) selected from    -   (a) a C₁₋₆ alkyl group (e.g., methyl, ethyl) optionally        substituted by 1 to 3 substituents selected from        -   (i) a halogen atom (e.g., a fluorine atom),        -   (ii) a cyano group,        -   (iii) a C₃₋₈ cycloalkyl group (e.g., cyclopropyl,            cyclobutyl),        -   (iv) a C₆₋₁₄ aryl group (e.g., phenyl) optionally            substituted by 1 to 3 substituents selected from a halogen            atom (e.g., a fluorine atom) and a C₁₋₆ alkoxy group (e.g.,            methoxy),        -   (v) a 5- or 6-membered monocyclic aromatic heterocyclic            group (e.g., pyridyl), and        -   (vi) a 3- to 8-membered monocyclic non-aromatic heterocyclic            group (e.g., oxetanyl) optionally substituted by 1 to 3 C₁₋₆            alkyl groups (e.g., methyl),    -   (b) a C₃₋₈ cycloalkyl group (e.g., cyclopropyl, cyclobutyl,        cyclopentyl) optionally substituted by 1 to 3 halogen atoms        (e.g., a fluorine atom),    -   (c) a C₆₋₁₄ aryl group (e.g., phenyl), and    -   (d) a 3- to 8-membered monocyclic non-aromatic heterocyclic        group (e.g., tetrahydropyranyl, oxetanyl, tetrahydrofuryl,        pyrrolidinyl) optionally substituted by 1 to 3 C₁₋₆ alkyl groups        (e.g., methyl),        (4) a C₃₋₈ cycloalkyl group (e.g., cyclopropyl) optionally        substituted by 1 to 3 C₆₋₁₄ aryl groups (e.g., phenyl),        (5) a C₆₋₁₄ aryl group (e.g., phenyl), or        (6) a 3- to 12-membered non-aromatic heterocyclic group        (preferably a 3- to 8-membered monocyclic non-aromatic        heterocyclic group (e.g., azetidinyl, pyrrolidinyl, piperidyl,        piperazinyl, morpholinyl, 1,1-dioxidothiomorpholinyl,        tetrahydropyranyl, 3-oxa-6-azabicyclo[3.1.1]heptyl,        8-oxa-3-azabicyclo[3.2.1]octyl, 2-oxa-5-azabicyclo[2.2.1]heptyl,        3-oxa-8-azabicyclo[3.2.1]octyl,        6-oxa-3-azabicyclo[3.1.1]heptyl),        3,7-dioxa-9-azabicyclo[3.3.1]nonyl)) optionally substituted by 1        to 5 substituents selected from    -   (a) a halogen atom (e.g., a fluorine atom),    -   (b) a cyano group,    -   (c) a hydroxy group,    -   (d) an oxo group,    -   (e) a carbamoyl group optionally mono- or di-substituted by C₁₋₆        alkyl group(s) (e.g., methyl),    -   (f) a C₁₋₆ alkyl group (e.g., methyl, ethyl, isopropyl)        optionally substituted by 1 to 3 substituents selected from        -   (i) a hydroxy group, and        -   (ii) a C₁₋₆ alkoxy group (e.g., methoxy),    -   (g) a C₁₋₆ alkoxy group (e.g., methoxy, ethoxy, isopropoxy)        optionally substituted by 1 to 3 halogen atoms (e.g., a fluorine        atom),    -   (h) a C₁₋₆ alkoxy-carbonyl group (e.g., methoxycarbonyl), and    -   (i) a C₆₋₁₄ aryl group (e.g., phenyl) optionally substituted by        1 to 3 halogen atoms (e.g., a fluorine atom).

R¹ is further more preferably a 3- to 8-membered monocyclic non-aromaticheterocyclic group (e.g., pyrrolidinyl) optionally substituted by 1 to 5substituents selected from

-   -   (a) a halogen atom (e.g., a fluorine atom),    -   (b) a cyano group,    -   (c) a carbamoyl group,    -   (d) a C₁₋₆ alkyl group (e.g., methyl) optionally substituted by        1 to 3 C₁₋₆ alkoxy groups (e.g., methoxy), and    -   (e) a C₁₋₆ alkoxy group (e.g., methoxy).

R¹ is still more preferably a 3- to 8-membered monocyclic non-aromaticheterocyclic group (e.g., pyrrolidinyl) optionally substituted by 1 to 5(preferably 1 to 3) substituents selected from

-   -   (a) a halogen atom (e.g., a fluorine atom),    -   (b) a cyano group,    -   (c) a carbamoyl group, and    -   (d) a C₁₋₆ alkyl group (e.g., methyl) optionally substituted by        1 to 3 C₁₋₆ alkoxy groups (e.g., methoxy).

In another embodiment, R¹ is further more preferably

(1) an amino group optionally mono- or di-substituted by substituent(s)selected from

-   -   (a) a C₁₋₆ alkyl group (e.g., methyl, ethyl) optionally        substituted by 1 to 3 substituents selected from        -   (i) a halogen atom (e.g., a fluorine atom), and        -   (ii) a C₆₋₁₄ aryl group (e.g., phenyl) optionally            substituted by 1 to 3 halogen atoms (e.g., a fluorine atom),            and    -   (b) a 3- to 8-membered monocyclic non-aromatic heterocyclic        group (e.g., tetrahydropyranyl, tetrahydrofuryl), or        (2) a 3- to 8-membered monocyclic non-aromatic heterocyclic        group (e.g., azetidinyl, pyrrolidinyl) optionally substituted by        1 to 5 substituents selected from    -   (a) a halogen atom (e.g., a fluorine atom),    -   (b) a cyano group,    -   (c) a carbamoyl group,    -   (d) a C₁₋₆ alkyl group (e.g., methyl), and    -   (e) a C₁₋₆ alkoxy group (e.g., methoxy).

R¹ is still more preferably

(1) an amino group optionally mono- or di-substituted by substituent(s)selected from

-   -   (a) a C₁₋₆ alkyl group (e.g., methyl, ethyl) optionally        substituted by 1 to 3 substituents selected from        -   (i) a halogen atom (e.g., a fluorine atom), and        -   (ii) a C₆₋₁₄ aryl group (e.g., phenyl) optionally            substituted by 1 to 3 halogen atoms (e.g., a fluorine atom),            and    -   (b) a 3- to 8-membered monocyclic non-aromatic heterocyclic        group (e.g., tetrahydropyranyl, tetrahydrofuryl), or        (2) a 3- to 8-membered monocyclic non-aromatic heterocyclic        group (e.g., azetidinyl, pyrrolidinyl) optionally substituted by        1 to 5 substituents selected from

(a) a halogen atom (e.g., a fluorine atom), and

(b) a cyano group.

R¹ is particularly preferably

(1) an amino group optionally mono- or di-substituted by substituent(s)selected from

-   -   (a) a C₁₋₆ alkyl group (e.g., methyl, ethyl) optionally        substituted by 1 to 3 substituents selected from        -   (i) a halogen atom (e.g., a fluorine atom), and        -   (ii) a C₆₋₁₄ aryl group (e.g., phenyl) optionally            substituted by 1 to 3 halogen atoms (e.g., a fluorine atom),            and    -   (b) a 3- to 8-membered monocyclic non-aromatic heterocyclic        group (e.g., tetrahydropyranyl, tetrahydrofuryl), or        (2) a 3- to 8-membered monocyclic non-aromatic heterocyclic        group (e.g., azetidinyl, pyrrolidinyl) optionally substituted by        1 to 3 halogen atoms (e.g., a fluorine atom).

In another embodiment, R¹ is further more preferably a 3- to 8-memberedmonocyclic non-aromatic heterocyclic group (e.g., pyrrolidinyl)optionally substituted by 1 to 5 substituents selected from

(a) a halogen atom (e.g., a fluorine atom),

(b) a cyano group,

(c) a carbamoyl group,

(d) a C₁₋₆ alkyl group (e.g., methyl), and

(e) a C₁₋₆ alkoxy group (e.g., methoxy).

R¹ is still more preferably a 3- to 8-membered monocyclic non-aromaticheterocyclic group (e.g., pyrrolidinyl) optionally substituted by 1 to 5substituents selected from

(a) a halogen atom (e.g., a fluorine atom), and

(b) a cyano group.

In the formula (I), R² is an optionally substituted C₆₋₁₄ aryl group, oran optionally substituted aromatic heterocyclic group.

The “C₆₋₁₄ aryl group” of the “optionally substituted C₆₋₁₄ aryl group”for R² optionally has 1 to 5 (preferably 1 to 3) substituents atsubstitutable position(s). Examples of the substituent includesubstituents selected from the above-mentioned Substituent Group B anoxo group. When the number of the substituents is plural, the respectivesubstituents may be the same or different.

The “aromatic heterocyclic group” of the “optionally substitutedaromatic heterocyclic group” for R² optionally has 1 to 5 (preferably 1to 3) substituents at substitutable position(s). Examples of thesubstituent include substituents selected from the above-mentionedSubstituent Group B excluding an oxo group. When the number of thesubstituents is plural, the respective substituents may be the same ordifferent.

R² is preferably

(1) a C₆₋₁₄ aryl group (e.g., phenyl) optionally substituted by 1 to 3substituents selected from

-   -   (a) a halogen atom (e.g., a fluorine atom, a chlorine atom), and    -   (b) a C₁₋₆ alkyl group (e.g., methyl) optionally substituted by        1 to 3 halogen atoms (e.g., a fluorine atom), or        (2) a 5- to 12-membered aromatic heterocyclic group (preferably        a 5- or 6-membered monocyclic aromatic heterocyclic group (e.g.,        pyrazolyl, oxazolyl, thiazolyl, thiadiazolyl, pyridyl), a 8- to        12-membered fused aromatic heterocyclic group (e.g., indazolyl,        benzothiazolyl)) optionally substituted by 1 to 3 substituents        selected from    -   (a) a halogen atom (e.g., a chlorine atom, a bromine atom),    -   (b) a cyano group,    -   (c) a C₁₋₆ alkyl group (e.g., methyl, ethyl) optionally        substituted by 1 to 3 halogen atoms (e.g., a fluorine atom), and    -   (d) a C₃₋₈ cycloalkyl group (e.g., cyclopropyl).

R² is more preferably

(1) a C₆₋₁₄ aryl group (e.g., phenyl) optionally substituted by 1 to 3substituents selected from

-   -   (a) a halogen atom (e.g., a fluorine atom, a chlorine atom), and    -   (b) a C₁₋₆ alkyl group (e.g., methyl) optionally substituted by        1 to 3 halogen atoms (e.g., a fluorine atom), or        (2) a 5- or 6-membered monocyclic aromatic heterocyclic group        (e.g., pyrazolyl, thiadiazolyl, pyridyl) optionally substituted        by 1 to 3 substituents selected from

(a) a halogen atom (e.g., a chlorine atom), and

(b) a C₁₋₆ alkyl group (e.g., methyl).

In another embodiment, R² is more preferably

(1) a C₆₋₁₄ aryl group (e.g., phenyl) optionally substituted by 1 to 3substituents selected from

(a) a halogen atom (e.g., a fluorine atom), and

(b) a C₁₋₆ alkyl group (e.g., methyl), or

(2) a 5- to 12-membered aromatic heterocyclic group (preferably a 5- or6-membered monocyclic aromatic heterocyclic group (e.g., pyrazolyl,oxazolyl, thiazolyl, thiadiazolyl, pyridyl), a 8- to 12-membered fusedaromatic heterocyclic group (e.g., benzothiazolyl)) optionallysubstituted by 1 to 3 substituents selected from

-   -   (a) a halogen atom (e.g., a chlorine atom, a bromine atom),    -   (b) a cyano group,    -   (c) a C₁₋₆ alkyl group (e.g., methyl) optionally substituted by        1 to 3 halogen atoms (e.g., a fluorine atom), and    -   (d) a C₃₋₈ cycloalkyl group (e.g., cyclopropyl).

R² is still more preferably a 5- or 6-membered monocyclic aromaticheterocyclic group (e.g., pyrazolyl, thiazolyl, thiadiazolyl, pyridyl(preferably pyrazolyl, thiadiazolyl, more preferably pyrazolyl))optionally substituted by 1 to 3 substituents selected from

(a) a halogen atom (e.g., a chlorine atom), and

(b) a C₁₋₆ alkyl group (e.g., methyl).

In another embodiment, R² is more preferably

(1) a C₆₋₁₄ aryl group (e.g., phenyl) optionally substituted by 1 to 3halogen atoms (e.g., a fluorine atom), or(2) a 5- or 6-membered monocyclic aromatic heterocyclic group (e.g.,pyrazolyl, thiazolyl, thiadiazolyl (preferably pyrazolyl, thiazolyl))optionally substituted by 1 to 3 substituents selected from

(a) a halogen atom (e.g., a chlorine atom, a bromine atom),

(b) a C₁₋₆ alkyl group (e.g., methyl), and

(c) a C₃₋₈ cycloalkyl group (e.g., cyclopropyl).

In the formula (I), X¹ is a carbon atom or a nitrogen atom.

X¹ is preferably a carbon atom.

In the formula (I), R³ is a hydrogen atom or a substituent when X¹ is acarbon atom, or absent when X¹ is a nitrogen atom.

The “substituent” for R³ means an optionally substituted hydrocarbongroup, an optionally substituted heterocyclic group, an optionallysubstituted hydroxy group, an optionally substituted sulfanyl group, anoptionally substituted amino group, an acyl group, a nitro group, acyano group or a halogen atom.

The C₁₋₁₀ alkyl group, C₂₋₁₀ alkenyl group and C₂₋₁₀ alkynyl group,which are exemplified as the above-mentioned “hydrocarbon group”,optionally have 1 to 5 (preferably 1 to 3) substituents at substitutableposition(s). Examples of the substituent include substituents selectedfrom the above-mentioned Substituent Group A. When the number of thesubstituents is plural, the respective substituents may be the same ordifferent.

The C₃₋₁₀ cycloalkyl group, C₃₋₁₀ cycloalkenyl group and C₄₋₁₀cycloalkadienyl group, which are exemplified as the above-mentioned“hydrocarbon group”, optionally have 1 to 5 (preferably 1 to 3)substituents at substitutable position(s). Examples of the substituentinclude substituents selected from the above-mentioned Substituent GroupB. When the number of the substituents is plural, the respectivesubstituents may be the same or different.

The C₆₋₁₄ aryl group, C₇₋₁₄ aralkyl group and C₈₋₁₃ arylalkenyl group,which are exemplified as the above-mentioned “hydrocarbon group”,optionally have 1 to 5 (preferably 1 to 3) substituents at substitutableposition(s). Examples of the substituent include substituents selectedfrom the above-mentioned Substituent Group B excluding an oxo group.When the number of the substituents is plural, the respectivesubstituents may be the same or different.

Examples of the “optionally substituted heterocyclic group” exemplifiedas the “substituent” for R³ include those similar to the “optionallysubstituted heterocyclic group” for R¹.

Examples of the “optionally substituted hydroxy group” exemplified asthe “substituent” for R³ include those similar to the “optionallysubstituted hydroxy group” for R¹.

Examples of the “optionally substituted sulfanyl group” exemplified asthe “substituent” for R³ include a sulfanyl group optionally substitutedby a substituent selected from a C₁₋₁₀ alkyl group, a C₂₋₁₀ alkenylgroup, a C₃₋₁₀ cycloalkyl group, a C₃₋₁₀ cycloalkenyl group, a C₆₋₁₄aryl group, a C₇₋₁₄ aralkyl group, a C₈₋₁₃ arylalkenyl group, a C₁₋₆alkyl-carbonyl group, a heterocyclic group (e.g., an aromaticheterocyclic group, a non-aromatic heterocyclic group) and the like,each of which is optionally substituted.

The C₁₋₁₀ alkyl group, C₂₋₁₀ alkenyl group and C₁₋₆ alkyl-carbonyl groupoptionally have 1 to 5 (preferably 1 to 3) substituents at substitutableposition(s). Examples of the substituent include substituents selectedfrom the above-mentioned Substituent Group A. When the number of thesubstituents is plural, the respective substituents may be the same ordifferent.

The C₃₋₁₀ cycloalkyl group, C₃₋₁₀ cycloalkenyl group and non-aromaticheterocyclic group optionally have 1 to 5 (preferably 1 to 3)substituents at substitutable position(s). Examples of the substituentinclude substituents selected from the above-mentioned Substituent GroupB. When the number of the substituents is plural, the respectivesubstituents may be the same or different.

The C₆₋₁₄ aryl group, C₇₋₁₄ aralkyl group, C₈₋₁₃ arylalkenyl group andaromatic heterocyclic group optionally have 1 to 5 (preferably 1 to 3)substituents at substitutable position(s). Examples of the substituentinclude substituents selected from the above-mentioned Substituent GroupB excluding oxo. When the number of the substituents is plural, therespective substituents may be the same or different.

Examples of the “optionally substituted amino group” exemplified as the“substituent” for R³ include those similar to the “optionallysubstituted amino group” for R¹.

Examples of the “acyl group” exemplified as the “substituent” for R³include those similar to the “acyl group” exemplified as the substituentof the “optionally substituted amino group” for R¹.

R³ is preferably

(1) a hydrogen atom, or(2) a halogen atom (e.g., a fluorine atom).

R³ is more preferably a hydrogen atom.

In the formula (I), Ring A is

each of which is optionally further substituted and optionally bridged.

Examples of the

in Ring A, each of which is optionally bridged, include8-azabicyclo[3.2.1]octane, 2,5-diazabicyclo[2.2.1]heptane,3-azabicyclo[3.1.0]hexane and the like. 8-Azabicyclo[3.2.1]octane and2,5-diazabicyclo[2.2.1]heptane are preferable.

The

in Ring A, each of which is optionally bridged, is preferably optionallybridged

particularly preferably

The

in Ring A, each of which is optionally bridged, optionally has 1 to 5(preferably 1 to 3) substituents at substitutable position(s). Examplesof the substituent include substituents selected from theabove-mentioned Substituent Group B. When the number of the substituentsis plural, the respective substituents may be the same or different.

Ring A is preferably

each of which is optionally bridged (e.g., the ring represented by theabove-mentioned formula, 8-azabicyclo[3.2.1]octane,2,5-diazabicyclo[2.2.1]heptane, 3-azabicyclo[3.1.0]hexane), each ofwhich is optionally further substituted by 1 to 5 (preferably 1 to 3)substituents selected from

(a) a halogen atom (e.g., a fluorine atom),

(b) a C₁₋₆ alkyl group (e.g., methyl), and

(c) an oxo group.

Ring A is more preferably

(1)

each of which is optionally further substituted by 1 to 3 substituentsselected from

(a) a halogen atom (e.g., a fluorine atom),

(b) a C₁₋₆ alkyl group (e.g., methyl), and

(c) an oxo group, or

(2) a 8-azabicyclo[3.2.1]octane ring, a 2,5-diazabicyclo[2.2.1]heptanering or a 3-azabicyclo[3.1.0]hexane ring.

Ring A is further more preferably

(1)

each of which is optionally further substituted by 1 to 3 substituentsselected from

(a) a halogen atom (e.g., a fluorine atom), and

(b) a C₁₋₆ alkyl group (e.g., methyl), or

(2) a 8-azabicyclo[3.2.1]octane ring or a 2,5-diazabicyclo[2.2.1]heptanering.

Ring A is still more preferably

Ring A is particularly preferably

Preferable examples of compound (I) include the following compounds.

[Compound A-1]

Compound (I) wherein

R¹ is an optionally substituted C₁₋₆ alkyl group, an optionallysubstituted C₁₋₆ alkoxy group, an optionally substituted amino group, anoptionally substituted C₃₋₈ cycloalkyl group, an optionally substitutedC₆₋₁₄ aryl group, or an optionally substituted non-aromatic heterocyclicgroup, or R¹ is bonded to the atom on Ring A to form, together with RingA, a spiro ring substituted by an oxo group and optionally furthersubstituted;

R² is an optionally substituted C₆₋₁₄ aryl group, or an optionallysubstituted aromatic heterocyclic group;

X¹ is a carbon atom or a nitrogen atom;

R³ is a hydrogen atom or a substituent when X¹ is a carbon atom, orabsent when X¹ is a nitrogen atom; and

Ring A is

each of which is optionally further substituted and optionally bridged.

[Compound A-2]

Compound (I) wherein

R¹ is an optionally substituted C₁₋₆ alkyl group, an optionallysubstituted C₁₋₆ alkoxy group, an optionally substituted amino group, anoptionally substituted C₃₋₈ cycloalkyl group, an optionally substitutedC₆₋₁₄ aryl group, or an optionally substituted non-aromatic heterocyclicgroup;

R² is an optionally substituted C₆₋₁₄ aryl group, or an optionallysubstituted aromatic heterocyclic group;

X¹ is a carbon atom or a nitrogen atom;

R³ is a hydrogen atom or a substituent when X¹ is a carbon atom, orabsent when X¹ is a nitrogen atom; and

Ring A is

each of which is optionally further substituted and optionally bridged.

[Compound B-1]

Compound (I) wherein

R¹ is

(1) a C₁₋₆ alkyl group (e.g., methyl, ethyl) optionally substituted by 1to 3 substituents selected from

-   -   (a) a cyano group,    -   (b) a C₆₋₁₄ aryl group (e.g., phenyl) optionally substituted by        1 to 3 C₁₋₆ alkoxy groups (e.g., methoxy),    -   (c) a C₆₋₁₄ aryloxy group (e.g., phenoxy),    -   (d) a C₃₋₈ cycloalkyl group (e.g., cyclopropyl),    -   (e) a 5- or 6-membered monocyclic aromatic heterocyclic group        (e.g., pyrazolyl),    -   (f) a 8- to 12-membered fused aromatic heterocyclic group (e.g.,        indazolyl), and    -   (g) a 3- to 8-membered monocyclic non-aromatic heterocyclic        group (e.g., dihydropyridyl) optionally substituted by 1 to 3        oxo groups,        (2) a C₁₋₆ alkoxy group (e.g., methoxy, tert-butoxy, preferably        a C₁₋₃ alkoxy group (e.g., methoxy)) optionally substituted by 1        to 3 C₆₋₁₄ aryl groups (e.g., phenyl),        (3) an amino group optionally mono- or di-substituted by        substituent(s) selected from    -   (a) a C₁₋₆ alkyl group (e.g., methyl, ethyl) optionally        substituted by 1 to 3 substituents selected from        -   (i) a halogen atom (e.g., a fluorine atom),        -   (ii) a cyano group,        -   (iii) a C₃₋₈ cycloalkyl group (e.g., cyclopropyl,            cyclobutyl),        -   (iv) a C₆₋₁₄ aryl group (e.g., phenyl) optionally            substituted by 1 to 3 halogen atoms (e.g., a fluorine atom),        -   (v) a 5- or 6-membered monocyclic aromatic heterocyclic            group (e.g., pyridyl), and        -   (vi) a 3- to 8-membered monocyclic non-aromatic heterocyclic            group (e.g., oxetanyl) optionally substituted by 1 to 3 C₁₋₆            alkyl groups (e.g., methyl),    -   (b) a C₃₋₈ cycloalkyl group (e.g., cyclopropyl, cyclobutyl,        cyclopentyl) optionally substituted by 1 to 3 halogen atoms        (e.g., a fluorine atom),    -   (c) a C₆₋₁₄ aryl group (e.g., phenyl), and    -   (d) a 3- to 8-membered monocyclic non-aromatic heterocyclic        group (e.g., tetrahydropyranyl, oxetanyl, tetrahydrofuryl,        pyrrolidinyl) optionally substituted by 1 to 3 C₁₋₆ alkyl groups        (e.g., methyl),        (4) a C₃₋₈ cycloalkyl group (e.g., cyclopropyl) optionally        substituted by 1 to 3 C₆₋₁₄ aryl groups (e.g., phenyl),        (5) a C₆₋₁₄ aryl group (e.g., phenyl), or        (6) a 3- to 12-membered non-aromatic heterocyclic group        (preferably a 3- to 8-membered monocyclic non-aromatic        heterocyclic group (e.g., azetidinyl, pyrrolidinyl, piperidyl,        piperazinyl, morpholinyl, 1,1-dioxidothiomorpholinyl,        tetrahydropyranyl, 3-oxa-6-azabicyclo[3.1.1]heptyl,        8-oxa-3-azabicyclo[3.2.1]octyl, 2-oxa-5-azabicyclo[2.2.1]heptyl,        3-oxa-8-azabicyclo[3.2.1]octyl,        6-oxa-3-azabicyclo[3.1.1]heptyl)) optionally substituted by 1 to        5 substituents selected from    -   (a) a halogen atom (e.g., a fluorine atom),    -   (b) a cyano group,    -   (c) a hydroxy group,    -   (d) an oxo group,    -   (e) a carbamoyl group,    -   (f) a C₁₋₆ alkyl group (e.g., methyl, ethyl, isopropyl)        optionally substituted by 1 to 3 substituents selected from        -   (i) a hydroxy group, and        -   (ii) a C₁₋₆ alkoxy group (e.g., methoxy),    -   (g) a C₁₋₆ alkoxy group (e.g., methoxy, ethoxy, isopropoxy),    -   (h) a C₁₋₆ alkoxy-carbonyl group (e.g., methoxycarbonyl), and    -   (i) a C₆₋₁₄ aryl group (e.g., phenyl) optionally substituted by        1 to 3 halogen atoms (e.g., a fluorine atom), or        R¹ is bonded to the atom on Ring A to form, together with Ring        A, a spiro ring (e.g., 2,8-diazaspiro[4.5]decane) substituted by        oxo and optionally further substituted by 1 to 3 C₁₋₆ alkyl        groups (e.g., methyl);

R² is

(1) a C₆₋₁₄ aryl group (e.g., phenyl) optionally substituted by 1 to 3substituents selected from

-   -   (a) a halogen atom (e.g., a fluorine atom, a chlorine atom), and    -   (b) a C₁₋₆ alkyl group (e.g., methyl) optionally substituted by        1 to 3 halogen atoms (e.g., a fluorine atom), or        (2) a 5- to 12-membered aromatic heterocyclic group (preferably        a 5- or 6-membered monocyclic aromatic heterocyclic group (e.g.,        pyrazolyl, oxazolyl, thiazolyl, thiadiazolyl, pyridyl), a 8- to        12-membered fused aromatic heterocyclic group (e.g., indazolyl,        benzothiazolyl)) optionally substituted by 1 to 3 substituents        selected from    -   (a) a halogen atom (e.g., a chlorine atom, a bromine atom),    -   (b) a cyano group,    -   (c) a C₁₋₆ alkyl group (e.g., methyl, ethyl) optionally        substituted by 1 to 3 halogen atoms (e.g., a fluorine atom), and    -   (d) a C₃₋₈ cycloalkyl group (e.g., cyclopropyl);

X¹ is a carbon atom or a nitrogen atom;

R³ is

(1) a hydrogen atom, or(2) a halogen atom (e.g., a fluorine atom); and

Ring A is

each of which is optionally bridged (e.g., the ring represented by theabove-mentioned formula, 8-azabicyclo[3.2.1]octane,2,5-diazabicyclo[2.2.1]heptane, 3-azabicyclo[3.1.0]hexane), each ofwhich is optionally further substituted by 1 to 5 (preferably 1 to 3)substituents selected from

(a) a halogen atom (e.g., a fluorine atom),

(b) a C₁₋₆ alkyl group (e.g., methyl), and

(c) an oxo group.

[Compound B-2]

Compound (I) wherein

R¹ is

(1) a C₁₋₆ alkyl group (e.g., methyl, ethyl) optionally substituted by 1to 3 substituents selected from

-   -   (a) a cyano group,    -   (b) a C₆₋₁₄ aryl group (e.g., phenyl) optionally substituted by        1 to 3 C₁₋₆ alkoxy groups (e.g., methoxy),    -   (c) a C₆₋₁₄ aryloxy group (e.g., phenoxy),    -   (d) a C₃₋₈ cycloalkyl group (e.g., cyclopropyl),    -   (e) a 5- or 6-membered monocyclic aromatic heterocyclic group        (e.g., pyrazolyl),    -   (f) a 8- to 12-membered fused aromatic heterocyclic group (e.g.,        indazolyl), and    -   (g) a 3- to 8-membered monocyclic non-aromatic heterocyclic        group (e.g., dihydropyridyl) optionally substituted by 1 to 3        oxo groups,        (2) a C₁₋₆ alkoxy group (e.g., methoxy, tert-butoxy, preferably        a C₁₋₃ alkoxy group (e.g., methoxy)) optionally substituted by 1        to 3 C₆₋₁₄ aryl groups (e.g., phenyl),        (3) an amino group optionally mono- or di-substituted by        substituent(s) selected from    -   (a) a C₁₋₆ alkyl group (e.g., methyl, ethyl) optionally        substituted by 1 to 3 substituents selected from        -   (i) a halogen atom (e.g., a fluorine atom),        -   (ii) a cyano group,        -   (iii) a C₃₋₈ cycloalkyl group (e.g., cyclopropyl,            cyclobutyl),        -   (iv) a C₆₋₁₄ aryl group (e.g., phenyl) optionally            substituted by 1 to 3 substituents selected from a halogen            atom (e.g., a fluorine atom) and a C₁₋₆ alkoxy group (e.g.,            methoxy),        -   (v) a 5- or 6-membered monocyclic aromatic heterocyclic            group (e.g., pyridyl), and        -   (vi) a 3- to 8-membered monocyclic non-aromatic heterocyclic            group (e.g., oxetanyl) optionally substituted by 1 to 3 C₁₋₆            alkyl groups (e.g., methyl),    -   (b) a C₃₋₈ cycloalkyl group (e.g., cyclopropyl, cyclobutyl,        cyclopentyl) optionally substituted by 1 to 3 halogen atoms        (e.g., a fluorine atom),    -   (c) a C₆₋₁₄ aryl group (e.g., phenyl), and    -   (d) a 3- to 8-membered monocyclic non-aromatic heterocyclic        group (e.g., tetrahydropyranyl, oxetanyl, tetrahydrofuryl,        pyrrolidinyl) optionally substituted by 1 to 3 C₁₋₆ alkyl groups        (e.g., methyl),        (4) a C₃₋₈ cycloalkyl group (e.g., cyclopropyl) optionally        substituted by 1 to 3 C₆₋₁₄ aryl groups (e.g., phenyl),        (5) a C₆₋₁₄ aryl group (e.g., phenyl), or        (6) a 3- to 12-membered non-aromatic heterocyclic group        (preferably a 3- to 8-membered monocyclic non-aromatic        heterocyclic group (e.g., azetidinyl, pyrrolidinyl, piperidyl,        piperazinyl, morpholinyl, 1,1-dioxidothiomorpholinyl,        tetrahydropyranyl, 3-oxa-6-azabicyclo[3.1.1]heptyl,        8-oxa-3-azabicyclo[3.2.1]octyl, 2-oxa-5-azabicyclo[2.2.1]heptyl,        3-oxa-8-azabicyclo[3.2.1]octyl,        6-oxa-3-azabicyclo[3.1.1]heptyl),        3,7-dioxa-9-azabicyclo[3.3.1]nonyl)) optionally substituted by 1        to 5 substituents selected from    -   (a) a halogen atom (e.g., a fluorine atom),    -   (b) a cyano group,    -   (c) a hydroxy group,    -   (d) an oxo group,    -   (e) a carbamoyl group optionally mono- or di-substituted by C₁₋₆        alkyl group(s) (e.g., methyl),    -   (f) a C₁₋₆ alkyl group (e.g., methyl, ethyl, isopropyl)        optionally substituted by 1 to 3 substituents selected from        -   (i) a hydroxy group, and        -   (ii) a C₁₋₆ alkoxy group (e.g., methoxy),    -   (g) a C₁₋₆ alkoxy group (e.g., methoxy, ethoxy, isopropoxy)        optionally substituted by 1 to 3 halogen atoms (e.g., a fluorine        atom),    -   (h) a C₁₋₆ alkoxy-carbonyl group (e.g., methoxycarbonyl), and    -   (i) a C₆₋₁₄ aryl group (e.g., phenyl) optionally substituted by        1 to 3 halogen atoms (e.g., a fluorine atom), or        R¹ is bonded to the atom on Ring A to form, together with Ring        A, a spiro ring (e.g., 2,8-diazaspiro[4.5]decane) substituted by        oxo and optionally further substituted by 1 to 3 C₁₋₆ alkyl        groups (e.g., methyl);

R² is

(1) a C₆₋₁₄ aryl group (e.g., phenyl) optionally substituted by 1 to 3substituents selected from

-   -   (a) a halogen atom (e.g., a fluorine atom, a chlorine atom), and    -   (b) a C₁₋₆ alkyl group (e.g., methyl) optionally substituted by        1 to 3 halogen atoms (e.g., a fluorine atom), or        (2) a 5- to 12-membered aromatic heterocyclic group (preferably        a 5- or 6-membered monocyclic aromatic heterocyclic group (e.g.,        pyrazolyl, oxazolyl, thiazolyl, thiadiazolyl, pyridyl), a 8- to        12-membered fused aromatic heterocyclic group (e.g., indazolyl,        benzothiazolyl)) optionally substituted by 1 to 3 substituents        selected from    -   (a) a halogen atom (e.g., a chlorine atom, a bromine atom),    -   (b) a cyano group,    -   (c) a C₁₋₆ alkyl group (e.g., methyl, ethyl) optionally        substituted by 1 to 3 halogen atoms (e.g., a fluorine atom), and    -   (d) a C₃₋₈ cycloalkyl group (e.g., cyclopropyl);

X¹ is a carbon atom or a nitrogen atom;

R³ is

(1) a hydrogen atom, or(2) a halogen atom (e.g., a fluorine atom); and

Ring A is

each if which is optionally bridged (e.g., the ring represented by theabove-mentioned formula, 8-azabicyclo[3.2.1]octane,2,5-diazabicyclo[2.2.1]heptane, 3-azabicyclo[3.1.0]hexane), each ofwhich is optionally further substituted by 1 to 5 (preferably 1 to 3)substituents selected from

(a) a halogen atom (e.g., a fluorine atom),

(b) a C₁₋₆ alkyl group (e.g., methyl), and

(c) an oxo group.

[Compound B-3]

Compound (I) wherein

R¹ is

(1) a C₁₋₆ alkyl group (e.g., methyl, ethyl) optionally substituted by 1to 3 substituents selected from

-   -   (a) a cyano group,    -   (b) a C₆₋₁₄ aryl group (e.g., phenyl) optionally substituted by        1 to 3 C₁₋₆ alkoxy groups (e.g., methoxy),    -   (c) a C₆₋₁₄ aryloxy group (e.g., phenoxy),    -   (d) a C₃₋₈ cycloalkyl group (e.g., cyclopropyl),    -   (e) a 5- or 6-membered monocyclic aromatic heterocyclic group        (e.g., pyrazolyl),    -   (f) a 8- to 12-membered fused aromatic heterocyclic group (e.g.,        indazolyl), and    -   (g) a 3- to 8-membered monocyclic non-aromatic heterocyclic        group (e.g., dihydropyridyl) optionally substituted by 1 to 3        oxo groups,        (2) a C₁₋₃ alkoxy group (e.g., methoxy) optionally substituted        by 1 to 3 C₆₋₁₄ aryl groups (e.g., phenyl),        (3) an amino group optionally mono- or di-substituted by        substituent(s) selected from    -   (a) a C₁₋₆ alkyl group (e.g., methyl, ethyl) optionally        substituted by 1 to 3 substituents selected from        -   (i) a halogen atom (e.g., a fluorine atom),        -   (ii) a cyano group,        -   (iii) a C₃₋₈ cycloalkyl group (e.g., cyclopropyl,            cyclobutyl),        -   (iv) a C₆₋₁₄ aryl group (e.g., phenyl) optionally            substituted by 1 to 3 substituents selected from a halogen            atom (e.g., a fluorine atom) and a C₁₋₆ alkoxy group (e.g.,            methoxy),        -   (v) a 5- or 6-membered monocyclic aromatic heterocyclic            group (e.g., pyridyl), and        -   (vi) a 3- to 8-membered monocyclic non-aromatic heterocyclic            group (e.g., oxetanyl) optionally substituted by 1 to 3 C₁₋₆            alkyl groups (e.g., methyl),    -   (b) a C₃₋₈ cycloalkyl group (e.g., cyclopropyl, cyclobutyl,        cyclopentyl) optionally substituted by 1 to 3 halogen atoms        (e.g., a fluorine atom),    -   (c) a C₆₋₁₄ aryl group (e.g., phenyl), and    -   (d) a 3- to 8-membered monocyclic non-aromatic heterocyclic        group (e.g., tetrahydropyranyl, oxetanyl, tetrahydrofuryl,        pyrrolidinyl) optionally substituted by 1 to 3 C₁₋₆ alkyl groups        (e.g., methyl),        (4) a C₃₋₈ cycloalkyl group (e.g., cyclopropyl) optionally        substituted by 1 to 3 C₆₋₁₄ aryl groups (e.g., phenyl),        (5) a C₆₋₁₄ aryl group (e.g., phenyl), or        (6) a 3- to 12-membered non-aromatic heterocyclic group        (preferably a 3- to 8-membered monocyclic non-aromatic        heterocyclic group (e.g., azetidinyl, pyrrolidinyl, piperidyl,        piperazinyl, morpholinyl, 1,1-dioxidothiomorpholinyl,        tetrahydropyranyl, 3-oxa-6-azabicyclo[3.1.1]heptyl,        8-oxa-3-azabicyclo[3.2.1]octyl, 2-oxa-5-azabicyclo[2.2.1]heptyl,        3-oxa-8-azabicyclo[3.2.1]octyl,        6-oxa-3-azabicyclo[3.1.1]heptyl),        3,7-dioxa-9-azabicyclo[3.3.1]nonyl)) optionally substituted by 1        to 5 substituents selected from    -   (a) a halogen atom (e.g., a fluorine atom),    -   (b) a cyano group,    -   (c) a hydroxy group,    -   (d) an oxo group,    -   (e) a carbamoyl group optionally mono- or di-substituted by C₁₋₆        alkyl group(s) (e.g., methyl),    -   (f) a C₁₋₆ alkyl group (e.g., methyl, ethyl, isopropyl)        optionally substituted by 1 to 3 substituents selected from        -   (i) a hydroxy group, and        -   (ii) a C₁₋₆ alkoxy group (e.g., methoxy),    -   (g) a C₁₋₆ alkoxy group (e.g., methoxy, ethoxy, isopropoxy)        optionally substituted by 1 to 3 halogen atoms (e.g., a fluorine        atom),    -   (h) a C₁₋₆ alkoxy-carbonyl group (e.g., methoxycarbonyl), and    -   (i) a C₆₋₁₄ aryl group (e.g., phenyl) optionally substituted by        1 to 3 halogen atoms (e.g., a fluorine atom), or        R¹ is bonded to the atom on Ring A to form, together with Ring        A, a spiro ring (e.g., 2,8-diazaspiro[4.5]decane) substituted by        oxo and optionally further substituted by 1 to 3 C₁₋₆ alkyl        groups (e.g., methyl);

R² is

(1) a C₆₋₁₄ aryl group (e.g., phenyl) optionally substituted by 1 to 3substituents selected from

-   -   (a) a halogen atom (e.g., a fluorine atom, a chlorine atom), and    -   (b) a C₁₋₆ alkyl group (e.g., methyl) optionally substituted by        1 to 3 halogen atoms (e.g., a fluorine atom), or        (2) a 5- to 12-membered aromatic heterocyclic group (preferably        a 5- or 6-membered monocyclic aromatic heterocyclic group (e.g.,        pyrazolyl, oxazolyl, thiazolyl, thiadiazolyl, pyridyl), a 8- to        12-membered fused aromatic heterocyclic group (e.g., indazolyl,        benzothiazolyl)) optionally substituted by 1 to 3 substituents        selected from    -   (a) a halogen atom (e.g., a chlorine atom, a bromine atom),    -   (b) a cyano group,    -   (c) a C₁₋₆ alkyl group (e.g., methyl, ethyl) optionally        substituted by 1 to 3 halogen atoms (e.g., a fluorine atom), and    -   (d) a C₃₋₈ cycloalkyl group (e.g., cyclopropyl);

X¹ is a carbon atom or a nitrogen atom;

R³ is

(1) a hydrogen atom, or(2) a halogen atom (e.g., a fluorine atom); and

Ring A is

each of which is optionally bridged (e.g., the ring represented by theabove-mentioned formula, 8-azabicyclo[3.2.1]octane,2,5-diazabicyclo[2.2.1]heptane, 3-azabicyclo[3.1.0]hexane), each ofwhich is optionally further substituted by 1 to 5 (preferably 1 to 3)substituents selected from

(a) a halogen atom (e.g., a fluorine atom),

(b) a C₁₋₆ alkyl group (e.g., methyl), and

(c) an oxo group.

[Compound B-4]

Compound (I) wherein

R¹ is

(1) a C₁₋₆ alkyl group (e.g., methyl, ethyl) optionally substituted by 1to 3 substituents selected from

-   -   (a) a cyano group,    -   (b) a C₆₋₁₄ aryl group (e.g., phenyl) optionally substituted by        1 to 3 C₁₋₆ alkoxy groups (e.g., methoxy),    -   (c) a C₆₋₁₄ aryloxy group (e.g., phenoxy),    -   (d) a C₃₋₈ cycloalkyl group (e.g., cyclopropyl),    -   (e) a pyrazolyl group,    -   (f) an indazolyl group, and    -   (g) a dihydropyridyl group optionally substituted by 1 to 3 oxo        groups,        (2) a C₁₋₆ alkoxy group (e.g., methoxy, tert-butoxy, preferably        a C₁₋₃ alkoxy group (e.g., methoxy)) optionally substituted by 1        to 3 C₆₋₁₄ aryl groups (e.g., phenyl),        (3) an amino group optionally mono- or di-substituted by        substituent(s) selected from    -   (a) a C₁₋₆ alkyl group (e.g., methyl, ethyl) optionally        substituted by 1 to 3 substituents selected from        -   (i) a halogen atom (e.g., a fluorine atom),        -   (ii) a cyano group,        -   (iii) a C₃₋₈ cycloalkyl group (e.g., cyclopropyl,            cyclobutyl),        -   (iv) a C₆₋₁₄ aryl group (e.g., phenyl) optionally            substituted by 1 to 3 substituents selected from a halogen            atom (e.g., a fluorine atom) and a C₁₋₆ alkoxy group (e.g.,            methoxy),        -   (v) a pyridyl group, and        -   (vi) an oxetanyl group optionally substituted by 1 to 3 C₁₋₆            alkyl groups (e.g., methyl),    -   (b) a C₃₋₈ cycloalkyl group (e.g., cyclopropyl, cyclobutyl,        cyclopentyl) optionally substituted by 1 to 3 halogen atoms        (e.g., a fluorine atom),    -   (c) a C₆₋₁₄ aryl group (e.g., phenyl), and    -   (d) a tetrahydropyranyl group, an oxetanyl group, a        tetrahydrofuryl group and a pyrrolidinyl group, each of which is        optionally substituted by 1 to 3 C₁₋₆ alkyl groups (e.g.,        methyl),        (4) a C₃₋₈ cycloalkyl group (e.g., cyclopropyl) optionally        substituted by 1 to 3 C₆₋₁₄ aryl groups (e.g., phenyl),        (5) a C₆₋₁₄ aryl group (e.g., phenyl), or        (6) a 3- to 8-membered monocyclic non-aromatic heterocyclic        group (e.g., azetidinyl, pyrrolidinyl, piperidyl, piperazinyl,        morpholinyl, 1,1-dioxidothiomorpholinyl, tetrahydropyranyl,        3-oxa-6-azabicyclo[3.1.1]heptyl, 8-oxa-3-azabicyclo[3.2.1]octyl,        2-oxa-5-azabicyclo[2.2.1]heptyl, 3-oxa-8-azabicyclo[3.2.1]octyl,        6-oxa-3-azabicyclo[3.1.1]heptyl) or a        3,7-dioxa-9-azabicyclo[3.3.1]nonyl group, each of which is        optionally substituted by 1 to 5 substituents selected from    -   (a) a halogen atom (e.g., a fluorine atom),    -   (b) a cyano group,    -   (c) a hydroxy group,    -   (d) an oxo group,    -   (e) a carbamoyl group optionally mono- or di-substituted by C₁₋₆        alkyl group(s) (e.g., methyl),    -   (f) a C₁₋₆ alkyl group (e.g., methyl, ethyl, isopropyl)        optionally substituted by 1 to 3 substituents selected from        -   (i) a hydroxy group, and        -   (ii) a C₁₋₆ alkoxy group (e.g., methoxy),    -   (g) a C₁₋₆ alkoxy group (e.g., methoxy, ethoxy, isopropoxy)        optionally substituted by 1 to 3 halogen atoms (e.g., a fluorine        atom),    -   (h) a C₁₋₆ alkoxy-carbonyl group (e.g., methoxycarbonyl), and    -   (i) a C₆₋₁₄ aryl group (e.g., phenyl) optionally substituted by        1 to 3 halogen atoms (e.g., a fluorine atom), or        R¹ is bonded to the atom on Ring A to form, together with Ring        A, a 2,8-diazaspiro[4.5]decane ring substituted by oxo and        optionally further substituted by 1 to 3 C₁₋₆ alkyl groups        (e.g., methyl);

R² is

(1) a C₆₋₁₄ aryl group (e.g., phenyl) optionally substituted by 1 to 3substituents selected from

-   -   (a) a halogen atom (e.g., a fluorine atom, a chlorine atom), and    -   (b) a C₁₋₆ alkyl group (e.g., methyl) optionally substituted by        1 to 3 halogen atoms (e.g., a fluorine atom), or        (2) a 5- or 6-membered monocyclic aromatic heterocyclic group        (e.g., pyrazolyl, oxazolyl, thiazolyl, thiadiazolyl, pyridyl) or        a 8- to 12-membered fused aromatic heterocyclic group (e.g.,        indazolyl, benzothiazolyl), each of which is optionally        substituted by 1 to 3 substituents selected from    -   (a) a halogen atom (e.g., a chlorine atom, a bromine atom),    -   (b) a cyano group,    -   (c) a C₁₋₆ alkyl group (e.g., methyl, ethyl) optionally        substituted by 1 to 3 halogen atoms (e.g., a fluorine atom), and    -   (d) a C₃₋₈ cycloalkyl group (e.g., cyclopropyl);

X¹ is a carbon atom or a nitrogen atom;

R³ is

(1) a hydrogen atom, or(2) a halogen atom (e.g., a fluorine atom); and

Ring A is

(1)

each of which is optionally further substituted by 1 to 3 substituentsselected from

(a) a halogen atom (e.g., a fluorine atom),

(b) a C₁₋₆ alkyl group (e.g., methyl), and

(c) an oxo group, or

(2) a 8-azabicyclo[3.2.1]octane ring, a 2,5-diazabicyclo[2.2.1]heptanering or a 3-azabicyclo[3.1.0]hexane ring.

[Compound B-5]

Compound (I) wherein

R¹ is

(1) a C₁₋₆ alkyl group (e.g., methyl, ethyl) optionally substituted by 1to 3 substituents selected from

-   -   (a) a cyano group,    -   (b) a C₆₋₁₄ aryl group (e.g., phenyl) optionally substituted by        1 to 3 C₁₋₆ alkoxy groups (e.g., methoxy),    -   (c) a C₆₋₁₄ aryloxy group (e.g., phenoxy),    -   (d) a C₃₋₈ cycloalkyl group (e.g., cyclopropyl),    -   (e) a pyrazolyl group,    -   (f) an indazolyl group, and    -   (g) a dihydropyridyl group optionally substituted by 1 to 3 oxo        groups,        (2) a C₁₋₃ alkoxy group (e.g., methoxy) optionally substituted        by 1 to 3 C₆₋₁₄ aryl groups (e.g., phenyl),        (3) an amino group optionally mono- or di-substituted by        substituent (s) selected from    -   (a) a C₁₋₆ alkyl group (e.g., methyl, ethyl) optionally        substituted by 1 to 3 substituents selected from        -   (i) a halogen atom (e.g., a fluorine atom),        -   (ii) a cyano group,        -   (iii) a C₃₋₈ cycloalkyl group (e.g., cyclopropyl,            cyclobutyl),        -   (iv) a C₆₋₁₄ aryl group (e.g., phenyl) optionally            substituted by 1 to 3 substituents selected from a halogen            atom (e.g., a fluorine atom) and a C₁₋₆ alkoxy group (e.g.,            methoxy),        -   (v) a pyridyl group, and        -   (vi) an oxetanyl group optionally substituted by 1 to 3 C₁₋₆            alkyl groups (e.g., methyl),    -   (b) a C₃₋₈ cycloalkyl group (e.g., cyclopropyl, cyclobutyl,        cyclopentyl) optionally substituted by 1 to 3 halogen atoms        (e.g., a fluorine atom),    -   (c) a C₆₋₁₄ aryl group (e.g., phenyl), and    -   (d) a tetrahydropyranyl group, an oxetanyl group, a        tetrahydrofuryl group and a pyrrolidinyl group, each of which is        optionally substituted by 1 to 3 C₁₋₆ alkyl groups (e.g.,        methyl),        (4) a C₃₋₈ cycloalkyl group (e.g., cyclopropyl) optionally        substituted by 1 to 3 C₆₋₁₄ aryl groups (e.g., phenyl),        (5) a C₆₋₁₄ aryl group (e.g., phenyl), or        (6) a 3- to 8-membered monocyclic non-aromatic heterocyclic        group (e.g., azetidinyl, pyrrolidinyl, piperidyl, piperazinyl,        morpholinyl, 1,1-dioxidothiomorpholinyl, tetrahydropyranyl,        3-oxa-6-azabicyclo[3.1.1]heptyl, 8-oxa-3-azabicyclo[3.2.1]octyl,        2-oxa-5-azabicyclo[2.2.1]heptyl, 3-oxa-8-azabicyclo[3.2.1]octyl,        6-oxa-3-azabicyclo[3.1.1]heptyl) or a        3,7-dioxa-9-azabicyclo[3.3.1]nonyl group, each of which is        optionally substituted by 1 to 5 substituents selected from    -   (a) a halogen atom (e.g., a fluorine atom),    -   (b) a cyano group,    -   (c) a hydroxy group,    -   (d) an oxo group,    -   (e) a carbamoyl group optionally mono- or di-substituted by C₁₋₆        alkyl group(s) (e.g., methyl),    -   (f) a C₁₋₆ alkyl group (e.g., methyl, ethyl, isopropyl)        optionally substituted by 1 to 3 substituents selected from        -   (i) a hydroxy group, and        -   (ii) a C₁₋₆ alkoxy group (e.g., methoxy),    -   (g) a C₁₋₆ alkoxy group (e.g., methoxy, ethoxy, isopropoxy)        optionally substituted by 1 to 3 halogen atoms (e.g., a fluorine        atom),    -   (h) a C₁₋₆ alkoxy-carbonyl group (e.g., methoxycarbonyl), and    -   (i) a C₆₋₁₄ aryl group (e.g., phenyl) optionally substituted by        1 to 3 halogen atoms (e.g., a fluorine atom), or        R¹ is bonded to the atom on Ring A to form, together with Ring        A, a 2,8-diazaspiro[4.5]decane ring substituted by oxo and        optionally further substituted by 1 to 3 C₁₋₆ alkyl groups        (e.g., methyl);

R² is

(1) a C₆₋₁₄ aryl group (e.g., phenyl) optionally substituted by 1 to 3substituents selected from

-   -   (a) a halogen atom (e.g., a fluorine atom, a chlorine atom), and    -   (b) a C₁₋₆ alkyl group (e.g., methyl) optionally substituted by        1 to 3 halogen atoms (e.g., a fluorine atom), or        (2) a 5- or 6-membered monocyclic aromatic heterocyclic group        (e.g., pyrazolyl, oxazolyl, thiazolyl, thiadiazolyl, pyridyl) or        a 8- to 12-membered fused aromatic heterocyclic group (e.g.,        indazolyl, benzothiazolyl), each of which is optionally        substituted by 1 to 3 substituents selected from    -   (a) a halogen atom (e.g., a chlorine atom, a bromine atom),    -   (b) a cyano group,    -   (c) a C₁₋₆ alkyl group (e.g., methyl, ethyl) optionally        substituted by 1 to 3 halogen atoms (e.g., a fluorine atom), and    -   (d) a C₃₋₈ cycloalkyl group (e.g., cyclopropyl);

X¹ is a carbon atom or a nitrogen atom;

R³ is

(1) a hydrogen atom, or(2) a halogen atom (e.g., a fluorine atom); and

Ring A is

(1)

each of which is optionally further substituted by 1 to 3 substituentsselected from

(a) a halogen atom (e.g., a fluorine atom),

(b) a C₁₋₆ alkyl group (e.g., methyl), and

(c) an oxo group, or

(2) a 8-azabicyclo[3.2.1]octane ring, a 2,5-diazabicyclo[2.2.1]heptanering or a 3-azabicyclo[3.1.0]hexane ring.

[Compound B-6]

Compound (I) wherein

R¹ is

(1) a C₁₋₆ alkyl group (e.g., methyl, ethyl) optionally substituted by 1to 3 substituents selected from

-   -   (a) a cyano group,    -   (b) a phenyl group optionally substituted by 1 to 3 C₁₋₆ alkoxy        groups (e.g., methoxy),    -   (c) a phenoxy group,    -   (d) a cyclopropyl group,    -   (e) a pyrazolyl group,    -   (f) an indazolyl group, and    -   (g) a dihydropyridyl group optionally substituted by 1 to 3 oxo        groups,        (2) a C₁₋₆ alkoxy group (e.g., methoxy, tert-butoxy, preferably        a C₁₋₃ alkoxy group (e.g., methoxy)) optionally substituted by 1        to 3 phenyl groups,        (3) an amino group optionally mono- or di-substituted by        substituent(s) selected from    -   (a) a C₁₋₆ alkyl group (e.g., methyl, ethyl) optionally        substituted by 1 to 3 substituents selected from        -   (i) a halogen atom (e.g., a fluorine atom),        -   (ii) a cyano group,        -   (iii) a cyclopropyl group,        -   (iv) a cyclobutyl group,        -   (v) a phenyl group optionally substituted by 1 to 3            substituents selected from a halogen atom (e.g., a fluorine            atom) and a C₁₋₆ alkoxy group (e.g., methoxy),        -   (vi) a pyridyl group, and        -   (vii) an oxetanyl group optionally substituted by 1 to 3            C₁₋₆ alkyl groups (e.g., methyl),    -   (b) a cyclopropyl group, a cyclobutyl group and a cyclopentyl        group, each of which is optionally substituted by 1 to 3 halogen        atoms (e.g., a fluorine atom),    -   (c) a phenyl group, and    -   (d) a tetrahydropyranyl group, an oxetanyl group, a        tetrahydrofuryl group and a pyrrolidinyl group, each of which is        optionally substituted by 1 to 3 C₁₋₆ alkyl groups (e.g.,        methyl),        (4) a cyclopropyl group optionally substituted by 1 to 3 phenyl        groups,        (5) a phenyl group, or        (6) an azetidinyl group, a pyrrolidinyl group, a piperidyl        group, a piperazinyl group, a morpholinyl group, a        1,1-dioxidothiomorpholinyl group, a tetrahydropyranyl group, a        3-oxa-6-azabicyclo[3.1.1]heptyl group, an        8-oxa-3-azabicyclo[3.2.1]octyl group, a        2-oxa-5-azabicyclo[2.2.1]heptyl group, a        3-oxa-8-azabicyclo[3.2.1]octyl group, a        6-oxa-3-azabicyclo[3.1.1]heptyl group or a        3,7-dioxa-9-azabicyclo[3.3.1]nonyl group, each of which is        optionally substituted by 1 to 5 substituents selected from    -   (a) a halogen atom (e.g., a fluorine atom),    -   (b) a cyano group,    -   (c) a hydroxy group,    -   (d) an oxo group,    -   (e) a carbamoyl group optionally mono- or di-substituted by C₁₋₆        alkyl group(s) (e.g., methyl),    -   (f) a C₁₋₆ alkyl group (e.g., methyl, ethyl, isopropyl)        optionally substituted by 1 to 3 substituents selected from        -   (i) a hydroxy group, and        -   (ii) a C₁₋₆ alkoxy group (e.g., methoxy),    -   (g) a C₁₋₆ alkoxy group (e.g., methoxy, ethoxy, isopropoxy)        optionally substituted by 1 to 3 halogen atoms (e.g., a fluorine        atom),    -   (h) a C₁₋₆ alkoxy-carbonyl group (e.g., methoxycarbonyl), and    -   (i) a phenyl group optionally substituted by 1 to 3 halogen        atoms (e.g., a fluorine atom), or        R¹ is bonded to the atom on Ring A to form, together with Ring        A, a 2,8-diazaspiro[4.5]decane ring substituted by oxo and        optionally further substituted by 1 to 3 C₁₋₆ alkyl groups        (e.g., methyl);

R² is

(1) a phenyl group optionally substituted by 1 to 3 substituentsselected from

-   -   (a) a halogen atom (e.g., a fluorine atom, a chlorine atom), and    -   (b) a C₁₋₆ alkyl group (e.g., methyl) optionally substituted by        1 to 3 halogen atoms (e.g., a fluorine atom), or        (2) a pyrazolyl group, an oxazolyl group, a thiazolyl group, a        thiadiazolyl group, a pyridyl group, an indazolyl group or a        benzothiazolyl group, each of which is optionally substituted by        1 to 3 substituents selected from    -   (a) a halogen atom (e.g., a chlorine atom, a bromine atom),    -   (b) a cyano group,    -   (c) a C₁₋₆ alkyl group (e.g., methyl, ethyl) optionally        substituted by 1 to 3 halogen atoms (e.g., a fluorine atom), and    -   (d) a cyclopropyl group;

X¹ is a carbon atom or a nitrogen atom;

R³ is

(1) a hydrogen atom, or(2) a halogen atom (e.g., a fluorine atom); and

Ring A is

(1)

each of which is optionally further substituted by 1 to 3 substituentsselected from

(a) a halogen atom (e.g., a fluorine atom),

(b) a C₁₋₆ alkyl group (e.g., methyl), and

(c) an oxo group, or

(2) a 8-azabicyclo[3.2.1]octane ring, a 2,5-diazabicyclo[2.2.1]heptanering or a 3-azabicyclo[3.1.0]hexane ring.

[Compound B-7]

Compound (I) wherein

R¹ is

(1) a C₁₋₆ alkyl group (e.g., methyl, ethyl) optionally substituted by 1to 3 substituents selected from

-   -   (a) a cyano group,    -   (b) a phenyl group optionally substituted by 1 to 3 C₁₋₆ alkoxy        groups (e.g., methoxy),    -   (c) a phenoxy group,    -   (d) a cyclopropyl group,    -   (e) a pyrazolyl group,    -   (f) an indazolyl group, and    -   (g) a dihydropyridyl group optionally substituted by 1 to 3 oxo        groups,        (2) a C₁₋₃ alkoxy group optionally substituted by 1 to 3 phenyl        groups (e.g., methoxy),        (3) an amino group optionally mono- or di-substituted by        substituent(s) selected from    -   (a) a C₁₋₆ alkyl group (e.g., methyl, ethyl) optionally        substituted by 1 to 3 substituents selected from        -   (i) a halogen atom (e.g., a fluorine atom),        -   (ii) a cyano group,        -   (iii) a cyclopropyl group,        -   (iv) a cyclobutyl group,        -   (v) a phenyl group optionally substituted by 1 to 3            substituents selected from a halogen atom (e.g., a fluorine            atom) and a C₁₋₆ alkoxy group (e.g., methoxy),        -   (vi) a pyridyl group, and        -   (vii) an oxetanyl group optionally substituted by 1 to 3            C₁₋₆ alkyl groups (e.g., methyl),    -   (b) a cyclopropyl group, a cyclobutyl group and a cyclopentyl        group, each of which is optionally substituted by 1 to 3 halogen        atoms (e.g., a fluorine atom),    -   (c) a phenyl group, and    -   (d) a tetrahydropyranyl group, an oxetanyl group, a        tetrahydrofuryl group and a pyrrolidinyl group, each of which is        optionally substituted by 1 to 3 C₁₋₆ alkyl groups (e.g.,        methyl),        (4) a cyclopropyl group optionally substituted by 1 to 3 phenyl        groups,        (5) a phenyl group, or        (6) an azetidinyl group, a pyrrolidinyl group, a piperidyl        group, a piperazinyl group, a morpholinyl group, a        1,1-dioxidothiomorpholinyl group, a tetrahydropyranyl group, a        3-oxa-6-azabicyclo[3.1.1]heptyl group, an        8-oxa-3-azabicyclo[3.2.1]octyl group, a        2-oxa-5-azabicyclo[2.2.1]heptyl group, a        3-oxa-8-azabicyclo[3.2.1]octyl group, a        6-oxa-3-azabicyclo[3.1.1]heptyl group or a        3,7-dioxa-9-azabicyclo[3.3.1]nonyl group, each of which is        optionally substituted by 1 to 5 substituents selected from    -   (a) a halogen atom (e.g., a fluorine atom),    -   (b) a cyano group,    -   (c) a hydroxy group,    -   (d) an oxo group,    -   (e) a carbamoyl group optionally mono- or di-substituted by C₁₋₆        alkyl group(s) (e.g., methyl),    -   (f) a C₁₋₆ alkyl group (e.g., methyl, ethyl, isopropyl)        optionally substituted by 1 to 3 substituents selected from        -   (i) a hydroxy group, and        -   (ii) a C₁₋₆ alkoxy group (e.g., methoxy),    -   (g) a C₁₋₆ alkoxy group (e.g., methoxy, ethoxy, isopropoxy)        optionally substituted by 1 to 3 halogen atoms (e.g., a fluorine        atom),    -   (h) a C₁₋₆ alkoxy-carbonyl group (e.g., methoxycarbonyl), and    -   (i) a phenyl group optionally substituted by 1 to 3 halogen        atoms (e.g., a fluorine atom), or        R¹ is bonded to the atom on Ring A to form, together with Ring        A, a 2,8-diazaspiro[4.5]decane ring substituted by oxo and        optionally further substituted by 1 to 3 C₁₋₆ alkyl groups        (e.g., methyl);

R² is

(1) a phenyl group optionally substituted by 1 to 3 substituentsselected from

-   -   (a) a halogen atom (e.g., a fluorine atom, a chlorine atom), and    -   (b) a C₁₋₆ alkyl group (e.g., methyl) optionally substituted by        1 to 3 halogen atoms (e.g., a fluorine atom), or        (2) a pyrazolyl group, an oxazolyl group, a thiazolyl group, a        thiadiazolyl group, a pyridyl group, an indazolyl group or a        benzothiazolyl group, each of which is optionally substituted by        1 to 3 substituents selected from    -   (a) a halogen atom (e.g., a chlorine atom, a bromine atom),    -   (b) a cyano group,    -   (c) a C₁₋₆ alkyl group (e.g., methyl, ethyl) optionally        substituted by 1 to 3 halogen atoms (e.g., a fluorine atom), and    -   (d) a cyclopropyl group;

X¹ is a carbon atom or a nitrogen atom;

R³ is

(1) a hydrogen atom, or(2) a halogen atom (e.g., a fluorine atom); and

Ring A is

(1)

each of which is optionally further substituted by 1 to 3 substituentsselected from

(a) a halogen atom (e.g., a fluorine atom),

(b) a C₁₋₆ alkyl group (e.g., methyl), and

(c) an oxo group, or

(2) a 8-azabicyclo[3.2.1]octane ring, a 2,5-diazabicyclo[2.2.1]heptanering or a 3-azabicyclo[3.1.0]hexane ring.

[Compound C-1]

Compound (I) wherein

R¹ is

(1) an amino group optionally mono- or di-substituted by substituent(s)selected from

-   -   (a) a C₁₋₆ alkyl group (e.g., methyl, ethyl) optionally        substituted by 1 to 3 substituents selected from        -   (i) a halogen atom (e.g., a fluorine atom), and        -   (ii) a C₆₋₁₄ aryl group (e.g., phenyl) optionally            substituted by 1 to 3 halogen atoms (e.g., a fluorine atom),            and    -   (b) a 3- to 8-membered monocyclic non-aromatic heterocyclic        group (e.g., tetrahydropyranyl, tetrahydrofuryl), or        (2) a 3- to 8-membered monocyclic non-aromatic heterocyclic        group (e.g., azetidinyl, pyrrolidinyl) optionally substituted by        1 to 5 substituents selected from    -   (a) a halogen atom (e.g., a fluorine atom),    -   (b) a cyano group,    -   (c) a carbamoyl group,    -   (d) a C₁₋₆ alkyl group (e.g., methyl), and    -   (e) a C₁₋₆ alkoxy group (e.g., methoxy);

R² is

(1) a C₆₋₁₄ aryl group (e.g., phenyl) optionally substituted by 1 to 3halogen atoms (e.g., a fluorine atom), or(2) a 5- or 6-membered monocyclic aromatic heterocyclic group (e.g.,pyrazolyl, thiazolyl, thiadiazolyl (preferably pyrazolyl, thiazolyl))optionally substituted by 1 to 3 substituents selected from

(a) a halogen atom (e.g., a chlorine atom, a bromine atom),

(b) a C₁₋₆ alkyl group (e.g., methyl), and

(c) a C₃₋₈ cycloalkyl group (e.g., cyclopropyl);

X¹ is a carbon atom or a nitrogen atom;

R³ is a hydrogen atom; and

Ring A is

[Compound C-2]

Compound (I) wherein

R¹ is

(1) an amino group optionally mono- or di-substituted by substituent(s)selected from

-   -   (a) a C₁₋₆ alkyl group (e.g., methyl, ethyl) optionally        substituted by 1 to 3 substituents selected from        -   (i) a halogen atom (e.g., a fluorine atom), and        -   (ii) a phenyl group optionally substituted by 1 to 3 halogen            atoms (e.g., a fluorine atom),    -   (b) a tetrahydropyranyl group, and    -   (c) a tetrahydrofuryl group, or        (2) an azetidinyl group or a pyrrolidinyl group, each of which        is optionally substituted by 1 to 5 substituents selected from

(a) a halogen atom (e.g., a fluorine atom),

(b) a cyano group,

(c) a carbamoyl group,

(d) a C₁₋₆ alkyl group (e.g., methyl), and

(e) a C₁₋₆ alkoxy group (e.g., methoxy);

R² is

(1) a phenyl group optionally substituted by 1 to 3 halogen atoms (e.g.,a fluorine atom), or(2) a pyrazolyl group, a thiazolyl group or a thiadiazolyl group, eachof which is optionally substituted by 1 to 3 substituents selected from

(a) a halogen atom (e.g., a chlorine atom, a bromine atom),

(b) a C₁₋₆ alkyl group (e.g., methyl), and

(c) a cyclopropyl group;

X¹ is a carbon atom or a nitrogen atom;

R³ is a hydrogen atom; and

Ring A is

[Compound D-1]

Compound (I) wherein

R¹ is

(1) an amino group optionally mono- or di-substituted by substituent(s)selected from

-   -   (a) a C₁₋₆ alkyl group (e.g., methyl, ethyl) optionally        substituted by 1 to 3 substituents selected from        -   (i) a halogen atom (e.g., a fluorine atom), and        -   (ii) a C₆₋₁₄ aryl group (e.g., phenyl) optionally            substituted by 1 to 3 halogen atoms (e.g., a fluorine atom),            and    -   (b) a 3- to 8-membered monocyclic non-aromatic heterocyclic        group (e.g., tetrahydropyranyl, tetrahydrofuryl), or        (2) a 3- to 8-membered monocyclic non-aromatic heterocyclic        group (e.g., azetidinyl, pyrrolidinyl) optionally substituted by        1 to 5 substituents selected from

(a) a halogen atom (e.g., a fluorine atom), and

(b) a cyano group;

R² is

(1) a C₆₋₁₄ aryl group (e.g., phenyl) optionally substituted by 1 to 3halogen atoms (e.g., a fluorine atom), or(2) a 5- or 6-membered monocyclic aromatic heterocyclic group (e.g.,pyrazolyl, thiazolyl, thiadiazolyl (preferably pyrazolyl, thiazolyl))optionally substituted by 1 to 3 substituents selected from

(a) a halogen atom (e.g., a chlorine atom, a bromine atom),

(b) a C₁₋₆ alkyl group (e.g., methyl), and

(c) a C₃₋₈ cycloalkyl group (e.g., cyclopropyl);

X¹ is a carbon atom or a nitrogen atom;

R³ is a hydrogen atom; and

Ring A is

[Compound D-2]

Compound (I) wherein

R¹ is

(1) an amino group optionally mono- or di-substituted by substituent(s)selected from

-   -   (a) a C₁₋₆ alkyl group (e.g., methyl, ethyl) optionally        substituted by 1 to 3 substituents selected from        -   (i) a halogen atom (e.g., a fluorine atom), and        -   (ii) a phenyl group optionally substituted by 1 to 3 halogen            atoms (e.g., a fluorine atom),    -   (b) a tetrahydropyranyl group, and    -   (c) a tetrahydrofuryl group, or        (2) an azetidinyl group or a pyrrolidinyl group, each of which        is optionally substituted by 1 to 5 substituents selected from

(a) a halogen atom (e.g., a fluorine atom), and

(b) a cyano group;

R² is

(1) a phenyl group optionally substituted by 1 to 3 halogen atoms (e.g.,a fluorine atom), or(2) a pyrazolyl group or a thiazolyl group, each of which is optionallysubstituted by 1 to 3 substituents selected from

(a) a halogen atom (e.g., a chlorine atom, a bromine atom),

(b) a C₁₋₆ alkyl group (e.g., methyl), and

(c) a cyclopropyl group;

X¹ is a carbon atom or a nitrogen atom;

R³ is a hydrogen atom; and

Ring A is

[Compound E-1]

Compound (I) wherein

R¹ is

(1) an amino group optionally mono- or di-substituted by substituent(s)selected from

-   -   (a) a C₁₋₆ alkyl group (e.g., methyl, ethyl) optionally        substituted by 1 to 3 substituents selected from        -   (i) a halogen atom (e.g., a fluorine atom), and        -   (ii) a C₆₋₁₄ aryl group (e.g., phenyl) optionally            substituted by 1 to 3 halogen atoms (e.g., a fluorine atom),            and    -   (b) a 3- to 8-membered monocyclic non-aromatic heterocyclic        group (e.g., tetrahydropyranyl, tetrahydrofuryl), or        (2) a 3- to 8-membered monocyclic non-aromatic heterocyclic        group (e.g., azetidinyl, pyrrolidinyl) optionally substituted by        1 to 3 halogen atoms (e.g., a fluorine atom);

R² is

(1) a C₆₋₁₄ aryl group (e.g., phenyl) optionally substituted by 1 to 3halogen atoms (e.g., a fluorine atom), or(2) a 5- or 6-membered monocyclic aromatic heterocyclic group (e.g.,pyrazolyl, thiazolyl, thiadiazolyl (preferably pyrazolyl, thiazolyl))optionally substituted by 1 to 3 substituents selected from

(a) a halogen atom (e.g., a chlorine atom, a bromine atom),

(b) a C₁₋₆ alkyl group (e.g., methyl), and

(c) a C₃₋₈ cycloalkyl group (e.g., cyclopropyl);

X¹ is a carbon atom or a nitrogen atom;

R³ is a hydrogen atom; and

Ring A is

[Compound E-2]

Compound (I) wherein

R¹ is

(1) an amino group optionally mono- or di-substituted by substituent(s)selected from

-   -   (a) a C₁₋₆ alkyl group (e.g., methyl, ethyl) optionally        substituted by 1 to 3 substituents selected from        -   (i) a halogen atom (e.g., a fluorine atom), and        -   (ii) a phenyl group optionally substituted by 1 to 3 halogen            atoms (e.g., a fluorine atom),    -   (b) a tetrahydropyranyl group, and    -   (c) a tetrahydrofuryl group, or        (2) an azetidinyl group or a pyrrolidinyl group, each of which        is optionally substituted by 1 to 3 halogen atoms (e.g., a        fluorine atom);

R² is

(1) a phenyl group optionally substituted by 1 to 3 halogen atoms (e.g.,a fluorine atom), or(2) a pyrazolyl group or a thiazolyl group, each of which is optionallysubstituted by 1 to 3 substituents selected from

(a) a halogen atom (e.g., a chlorine atom, a bromine atom),

(b) a C₁₋₆ alkyl group (e.g., methyl), and

(c) a cyclopropyl group;

X¹ is a carbon atom or a nitrogen atom;

R³ is a hydrogen atom; and

Ring A is

[Compound F-1]

Compound (I) wherein

R¹ is a 3- to 8-membered monocyclic non-aromatic heterocyclic group(e.g., pyrrolidinyl) optionally substituted by 1 to 5 substituentsselected from

(a) a halogen atom (e.g., a fluorine atom),

(b) a cyano group,

(c) a carbamoyl group,

(d) a C₁₋₆ alkyl group (e.g., methyl), and

(e) a C₁₋₆ alkoxy group (e.g., methoxy);

R² is a 5- or 6-membered monocyclic aromatic heterocyclic group (e.g.,pyrazolyl, thiazolyl, thiadiazolyl, pyridyl (preferably pyrazolyl,thiadiazolyl, more preferably pyrazolyl)) optionally substituted by 1 to3 substituents selected from

(a) a halogen atom (e.g., a chlorine atom), and

(b) a C₁₋₆ alkyl group (e.g., methyl);

X¹ is a carbon atom;

R³ is a hydrogen atom; and

Ring A is

[Compound F-2]

Compound (I) wherein

R¹ is a pyrrolidinyl group optionally substituted by 1 to 5 substituentsselected from

(a) a halogen atom (e.g., a fluorine atom),

(b) a cyano group,

(c) a carbamoyl group,

(d) a C₁₋₆ alkyl group (e.g., methyl), and

(e) a C₁₋₆ alkoxy group (e.g., methoxy);

R² is a pyrazolyl group or a thiadiazolyl group, each of which isoptionally substituted by 1 to 3 substituents selected from

(a) a halogen atom (e.g., a chlorine atom), and

(b) a C₁₋₆ alkyl group (e.g., methyl);

X¹ is a carbon atom;

R³ is a hydrogen atom; and

Ring A is

[Compound G-1]

Compound (I) wherein

R¹ is a 3- to 8-membered monocyclic non-aromatic heterocyclic group(e.g., pyrrolidinyl) optionally substituted by 1 to 5 substituentsselected from

(a) a halogen atom (e.g., a fluorine atom), and

(b) a cyano group;

R² is a 5- or 6-membered monocyclic aromatic heterocyclic group (e.g.,pyrazolyl, thiazolyl, thiadiazolyl, pyridyl (preferably pyrazolyl,thiadiazolyl, more preferably pyrazolyl)) optionally substituted by 1 to3 substituents selected from

(a) a halogen atom (e.g., a chlorine atom), and

(b) a C₁₋₆ alkyl group (e.g., methyl);

X¹ is a carbon atom;

R³ is a hydrogen atom; and

Ring A is

[Compound G-2]

Compound (I) wherein

R¹ is a pyrrolidinyl group optionally substituted by 1 to 5 substituentsselected from

(a) a halogen atom (e.g., a fluorine atom), and

(b) a cyano group;

R² is a pyrazolyl group optionally substituted by 1 to 3 substituentsselected from

(a) a halogen atom (e.g., a chlorine atom), and

(b) a C₁₋₆ alkyl group (e.g., methyl);

X¹ is a carbon atom;

R³ is a hydrogen atom; and

Ring A is

[Compound H-1]

Compound (I) wherein

R¹ is

(1) a C₁₋₆ alkyl group (e.g., methyl, ethyl) optionally substituted by 1to 3 substituents selected from

-   -   (a) a C₃₋₈ cycloalkyl group (e.g., cyclopropyl), and    -   (b) a 8- to 12-membered fused aromatic heterocyclic group (e.g.,        indazolyl),        (2) a C₁₋₆ alkoxy group (preferably a C₁₋₃ alkoxy group (e.g.,        methoxy)) optionally substituted by 1 to 3 C₆₋₁₄ aryl groups        (e.g., phenyl),        (3) an amino group optionally mono- or di-substituted by        substituent(s) selected from    -   (a) a C₁₋₆ alkyl group (e.g., methyl, ethyl) optionally        substituted by 1 to 3 substituents selected from        -   (i) a halogen atom (e.g., a fluorine atom),        -   (ii) a C₆₋₁₄ aryl group (e.g., phenyl) optionally            substituted by 1 to 3 halogen atoms (e.g., a fluorine atom),        -   (iii) a 5- or 6-membered monocyclic aromatic heterocyclic            group (e.g., pyridyl), and        -   (iv) a 3- to 8-membered monocyclic non-aromatic heterocyclic            group (e.g., oxetanyl) optionally substituted by 1 to 3 C₁₋₆            alkyl groups (e.g., methyl),    -   (b) a C₃₋₈ cycloalkyl group (e.g., cyclopropyl, cyclopentyl),    -   (c) a 3- to 8-membered monocyclic non-aromatic heterocyclic        group (e.g., tetrahydropyranyl, tetrahydrofuryl), and    -   (d) a C₆₋₁₄ aryl group (e.g., phenyl),        (4) a C₃₋₈ cycloalkyl group (e.g., cyclopropyl), or        (5) a 3- to 8-membered monocyclic non-aromatic heterocyclic        group (e.g., azetidinyl, pyrrolidinyl,        1,1-dioxidothiomorpholinyl, 3-oxa-6-azabicyclo[3.1.1]heptyl)        optionally substituted by 1 to 5 substituents selected from    -   (a) a halogen atom (e.g., a fluorine atom),    -   (b) a cyano group,    -   (c) a carbamoyl group,    -   (d) a C₁₋₆ alkyl group (e.g., methyl, isopropyl) optionally        substituted by 1 to 3 C₁₋₆ alkoxy groups (e.g., methoxy),    -   (e) a C₁₋₆ alkoxy group (e.g., methoxy), and    -   (f) a C₆₋₁₄ aryl group (e.g., phenyl) optionally substituted by        1 to 3 halogen atoms (e.g., a fluorine atom), or        R¹ is bonded to the atom on Ring A to form, together with Ring        A, a spiro ring (e.g., 2,8-diazaspiro[4.5]decane) substituted by        oxo and optionally further substituted by 1 to 3 C₁₋₆ alkyl        groups (e.g., methyl);

R² is

(1) a C₆₋₁₄ aryl group (e.g., phenyl) optionally substituted by 1 to 3substituents selected from

(a) a halogen atom (e.g., a fluorine atom), and

(b) a C₁₋₆ alkyl group (e.g., methyl), or

(2) a 5- to 12-membered aromatic heterocyclic group (preferably a 5- or6-membered monocyclic aromatic heterocyclic group (e.g., pyrazolyl,oxazolyl, thiazolyl, thiadiazolyl, pyridyl), a 8- to 12-membered fusedaromatic heterocyclic group (e.g., benzothiazolyl)) optionallysubstituted by 1 to 3 substituents selected from

-   -   (a) a halogen atom (e.g., a chlorine atom, a bromine atom),    -   (b) a cyano group,    -   (c) a C₁₋₆ alkyl group (e.g., methyl) optionally substituted by        1 to 3 halogen atoms (e.g., a fluorine atom), and    -   (d) a C₃₋₈ cycloalkyl group (e.g., cyclopropyl);

X¹ is a carbon atom or a nitrogen atom;

R³ is

(1) a hydrogen atom, or(2) a halogen atom (e.g., a fluorine atom); and

Ring A is

(1)

each of which is optionally further substituted by 1 to 3 substituentsselected from

(a) a halogen atom (e.g., a fluorine atom), and

(b) a C₁₋₆ alkyl group (e.g., methyl), or

(2) a 8-azabicyclo[3.2.1]octane ring or a 2,5-diazabicyclo[2.2.1]heptanering.

[Compound H-2]

Compound (I) wherein

R¹ is

(1) a C₁₋₆ alkyl group (e.g., methyl, ethyl) optionally substituted by 1to 3 substituents selected from

(a) a cyclopropyl group, and

(b) an indazolyl group,

(2) a C₁₋₆ alkoxy group optionally substituted by 1 to 3 phenyl groups(preferably C₁₋₃ alkoxy group (e.g., methoxy)),(3) an amino group optionally mono- or di-substituted by substituent(s)selected from

-   -   (a) a C₁₋₆ alkyl group (e.g., methyl, ethyl) optionally        substituted by 1 to 3 substituents selected from        -   (i) a halogen atom (e.g., a fluorine atom),        -   (ii) a phenyl group optionally substituted by 1 to 3 halogen            atoms (e.g., a fluorine atom),        -   (iii) a pyridyl group, and        -   (iv) an oxetanyl group optionally substituted by 1 to 3 C₁₋₆            alkyl groups (e.g., methyl),    -   (b) a cyclopropyl group,    -   (c) a cyclopentyl group,    -   (d) a tetrahydropyranyl group,    -   (e) a tetrahydrofuryl group, and    -   (f) a phenyl group,        (4) a cyclopropyl group, or        (5) an azetidinyl group, a pyrrolidinyl group, a        1,1-dioxidothiomorpholinyl group or a        3-oxa-6-azabicyclo[3.1.1]heptyl group, each of which is        optionally substituted by 1 to 5 substituents selected from    -   (a) a halogen atom (e.g., a fluorine atom),    -   (b) a cyano group,    -   (c) a carbamoyl group,    -   (d) a C₁₋₆ alkyl group (e.g., methyl, isopropyl) optionally        substituted by 1 to 3 C₁₋₆ alkoxy groups (e.g., methoxy),    -   (e) a C₁₋₆ alkoxy group (e.g., methoxy), and    -   (f) a phenyl group optionally substituted by 1 to 3 halogen        atoms (e.g., a fluorine atom), or        R¹ is bonded to the atom on Ring A to form, together with Ring        A, a 2,8-diazaspiro[4.5]decane ring substituted by oxo and        optionally further substituted by 1 to 3 C₁₋₆ alkyl groups        (e.g., methyl);

R² is

(1) a phenyl group optionally substituted by 1 to 3 substituentsselected from

(a) a halogen atom (e.g., a fluorine atom), and

(b) a C₁₋₆ alkyl group (e.g., methyl), or

(2) a pyrazolyl group, an oxazolyl group, a thiazolyl group, athiadiazolyl group, a pyridyl group or a benzothiazolyl group, each ofwhich is optionally substituted by 1 to 3 substituents selected from

-   -   (a) a halogen atom (e.g., a chlorine atom, a bromine atom),    -   (b) a cyano group,    -   (c) a C₁₋₆ alkyl group (e.g., methyl) optionally substituted by        1 to 3 halogen atoms (e.g., a fluorine atom), and    -   (d) a cyclopropyl group;

X¹ is a carbon atom or a nitrogen atom;

R³ is

(1) a hydrogen atom, or(2) a halogen atom (e.g., a fluorine atom); and

Ring A is

(1)

each of which is optionally further substituted by 1 to 3 substituentsselected from

(a) a halogen atom (e.g., a fluorine atom), and

(b) a C₁₋₆ alkyl group (e.g., methyl), or

(2) a 8-azabicyclo[3.2.1]octane ring or a 2,5-diazabicyclo[2.2.1]heptanering.

[Compound I-1]

Compound (I) wherein

R¹ is a 3- to 8-membered monocyclic non-aromatic heterocyclic group(e.g., pyrrolidinyl) optionally substituted by 1 to 5 (preferably 1 to3) substituents selected from

-   -   (a) a halogen atom (e.g., a fluorine atom),    -   (b) a cyano group,    -   (c) a carbamoyl group, and    -   (d) a C₁₋₆ alkyl group (e.g., methyl) optionally substituted by        1 to 3 C₁₋₆ alkoxy groups (e.g., methoxy);

R² is a 5- or 6-membered monocyclic aromatic heterocyclic group (e.g.,pyrazolyl, thiazolyl, thiadiazolyl, pyridyl (preferably pyrazolyl,thiadiazolyl, more preferably pyrazolyl)) optionally substituted by 1 to3 substituents selected from

(a) a halogen atom (e.g., a chlorine atom), and

(b) a C₁₋₆ alkyl group (e.g., methyl);

X¹ is a carbon atom;

R³ is a hydrogen atom; and

Ring A is

[Compound I-2]

Compound (I) wherein

R¹ is a pyrrolidinyl group optionally substituted by 1 to 3 substituentsselected from

-   -   (a) a halogen atom (e.g., a fluorine atom),    -   (b) a cyano group,    -   (c) a carbamoyl group, and    -   (d) a C₁₋₆ alkyl group (e.g., methyl) optionally substituted by        1 to 3 C₁₋₆ alkoxy groups (e.g., methoxy);

R² is a pyrazolyl group, a thiazolyl group, a thiadiazolyl group or apyridyl group, each of which is optionally substituted by 1 to 3substituents selected from

(a) a halogen atom (e.g., a chlorine atom), and

(b) a C₁₋₆ alkyl group (e.g., methyl);

X¹ is a carbon atom;

R³ is a hydrogen atom; and

Ring A is

[Compound J-1]

Compound (I) wherein

R¹ is a 3- to 8-membered monocyclic non-aromatic heterocyclic group(e.g., pyrrolidinyl) optionally substituted by 1 to 5 substituentsselected from

-   -   (a) a halogen atom (e.g., a fluorine atom),    -   (b) a cyano group,    -   (c) a carbamoyl group,    -   (d) a C₁₋₆ alkyl group (e.g., methyl) optionally substituted by        1 to 3 C₁₋₆ alkoxy groups (e.g., methoxy), and    -   (e) a C₁₋₆ alkoxy group (e.g., methoxy);

R² is

(1) a C₆₋₁₄ aryl group (e.g., phenyl) optionally substituted by 1 to 3substituents selected from

-   -   (a) a halogen atom (e.g., a fluorine atom, a chlorine atom), and    -   (b) a C₁₋₆ alkyl group (e.g., methyl) optionally substituted by        1 to 3 halogen atoms (e.g., a fluorine atom), or        (2) a 5- or 6-membered monocyclic aromatic heterocyclic group        (e.g., pyrazolyl, thiadiazolyl, pyridyl) optionally substituted        by 1 to 3 substituents selected from

(a) a halogen atom (e.g., a chlorine atom), and

(b) a C₁₋₆ alkyl group (e.g., methyl);

X¹ is a carbon atom;

R³ is a hydrogen atom; and

Ring A is

[Compound J-2]

Compound (I) wherein

R¹ is a pyrrolidinyl group optionally substituted by 1 to 5 substituentsselected from

-   -   (a) a halogen atom (e.g., a fluorine atom),    -   (b) a cyano group,    -   (c) a carbamoyl group,    -   (d) a C₁₋₆ alkyl group (e.g., methyl) optionally substituted by        1 to 3 C₁₋₆ alkoxy groups (e.g., methoxy), and    -   (e) a C₁₋₆ alkoxy group (e.g., methoxy);

R² is

(1) a phenyl group optionally substituted by 1 to 3 substituentsselected from

-   -   (a) a halogen atom (e.g., a fluorine atom, a chlorine atom), and    -   (b) a C₁₋₆ alkyl group (e.g., methyl) optionally substituted by        1 to 3 halogen atoms (e.g., a fluorine atom), or        (2) a pyrazolyl group, a thiadiazolyl group or a pyridyl group,        each of which is optionally substituted by 1 to 3 substituents        selected from

(a) a halogen atom (e.g., a chlorine atom), and

(b) a C₁₋₆ alkyl group (e.g., methyl);

X¹ is a carbon atom;

R³ is a hydrogen atom; and

Ring A is

[Compound K-1]

Compound (I) which is selected from

-   (2R)-1-((1-(4-(4-methyl-1H-pyrazol-1-yl)pyridin-3-yl)piperidin-4-yl)carbonyl)pyrrolidine-2-carbonitrile,-   (2R)-1-((1-(4-(4-chloro-1H-pyrazol-1-yl)pyridin-3-yl)piperidin-4-yl)carbonyl)pyrrolidine-2-carbonitrile,-   (2R)-4,4-difluoro-1-((1-(4-(4-methyl-1H-pyrazol-1-yl)pyridin-3-yl)piperidin-4-yl)carbonyl)pyrrolidine-2-carbonitrile,-   (3-fluoroazetidin-1-yl)(1-(4-(4-fluorophenyl)pyrimidin-5-yl)piperidin-4-yl)    methanone,-   (1-(4-(4-chloro-1H-pyrazol-1-yl)pyridin-3-yl)piperidin-4-yl)(3-fluoroazetidin-1-yl)methanone,-   (1-(4-(4-chloro-1H-pyrazol-1-yl)pyridin-3-yl)piperidin-4-yl)((3S)-3-fluoropyrrolidin-1-yl)methanone,-   (1-(4-(4-fluorophenyl)pyrimidin-5-yl)piperidin-4-yl)((3S)-3-fluoropyrrolidin-1-yl)methanone,-   N-benzyl-N-(2-fluoroethyl)-4-(4-phenylpyrimidin-5-yl)piperazine-1-carboxamide,-   N-(4-fluorobenzyl)-N-(2-fluoroethyl)-4-(4-(4-methyl-1H-pyrazol-1-yl)pyridin-3-yl)piperazine-1-carboxamide,-   ((3S)-3-fluoropyrrolidin-1-yl)(1-(4-(5-methyl-1,3-thiazol-2-yl)pyridin-3-yl)piperidin-4-yl)    methanone,-   (3-fluoroazetidin-1-yl)(1-(4-(5-methyl-1,3-thiazol-2-yl)pyridin-3-yl)piperidin-4-yl)methanone,-   (1-(4-(4-bromo-1H-pyrazol-1-yl)pyridin-3-yl)piperidin-4-yl)(3-fluoroazetidin-1-yl)methanone,    and-   (1-(4-(4-cyclopropyl-1H-pyrazol-1-yl)pyridin-3-yl)piperidin-4-yl)(3-fluoroazetidin-1-yl)methanone.

[Compound K-2]

-   (2R)-1-((1-(4-(4-methyl-1H-pyrazol-1-yl)pyridin-3-yl)piperidin-4-yl)carbonyl)pyrrolidine-2-carbonitrile

[Compound K-3]

-   (2R)-1-((1-(4-(4-chloro-1H-pyrazol-1-yl)pyridin-3-yl)piperidin-4-yl)carbonyl)pyrrolidine-2-carbonitrile

[Compound K-4]

-   (2R)-4,4-difluoro-1-((1-(4-(4-methyl-1H-pyrazol-1-yl)pyridin-3-yl)piperidin-4-yl)carbonyl)pyrrolidine-2-carbonitrile

When compound (I) is in a form of a salt, examples thereof include metalsalts, an ammonium salt, salts with organic base, salts with inorganicacid, salts with organic acid, salts with basic or acidic amino acid,and the like. Preferable examples of the metal salt include alkali metalsalts such as sodium salt, potassium salt and the like; alkaline earthmetal salts such as calcium salt, magnesium salt, barium salt and thelike; an aluminum salt, and the like. Preferable examples of the saltwith organic base include salts with trimethylamine, triethylamine,pyridine, picoline, 2,6-lutidine, ethanolamine, diethanolamine,triethanolamine, cyclohexylamine, dicyclohexylamine,N,N′-dibenzylethylenediamine and the like. Preferable examples of thesalt with inorganic acid include salts with hydrochloric acid,hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid and thelike. Preferable examples of the salt with organic acid include saltswith formic acid, acetic acid, trifluoroacetic acid, phthalic acid,fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid,succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid,p-toluenesulfonic acid and the like. Preferable examples of the saltwith basic amino acid include salts with arginine, lysine, ornithine andthe like. Preferable examples of the salt with acidic amino acid includesalts with aspartic acid, glutamic acid and the like.

Among them, a pharmaceutically acceptable salt is preferable. Forexample, when a compound has an acidic functional group, examplesthereof include inorganic salts such as alkali metal salts (e.g., sodiumsalt, potassium salt etc.), alkaline earth metal salts (e.g., calciumsalt, magnesium salt etc.) and the like, ammonium salt etc., and when acompound has a basic functional group, examples thereof include saltswith inorganic acid such as hydrochloric acid, hydrobromic acid, nitricacid, sulfuric acid, phosphoric acid and the like, and salts withorganic acid such as acetic acid, phthalic acid, fumaric acid, oxalicacid, tartaric acid, maleic acid, citric acid, succinic acid,methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid andthe like.

[Production Method]

The compound of the present invention and the starting compounds can beproduced by a method known per se, for example, by method shown in thefollowing scheme and the like. In the following, the “room temperature”generally means 0-40° C. and, unless otherwise specified, each symbol inthe chemical formulas described in the schemes is as defined above. Inthe formulas, each compound includes salts, and examples of such saltinclude those similar to the salts of the compound of the presentinvention and the like. The compound obtained in each step can be useddirectly as the reaction mixture or as a crude product for the nextreaction. It can also be isolated from a reaction mixture by aconventional method, and can be easily purified by a separation meanssuch as recrystallization, distillation, chromatography and the like.When the compound in the formula is commercially available, acommercially available product can also be used directly. When each ringin the formula (I) has a substituent, the corresponding precursor alsohas a similar substituent.

When the starting compound has an amino group, a carboxyl group, ahydroxy group or a heterocyclic group, these groups may be protected bya protecting group generally used in peptide chemistry and the like. Byremoving the protecting group as necessary after the reaction, theobjective compound can be obtained. The protection and deprotection canbe performed according to a method known per se, for example, the methoddescribed in “Protective Groups in Organic Synthesis, 3rd Ed”, JohnWiley and Sons, Inc. (1999) (Theodora W. Greene, Peter G. M. Wuts).Preferable examples of the protecting group include atert-butylcarbamate group, a benzylcarbamate group, a benzyl group, amethyl group, an ethyl group, a tert-butyl and the like.

Examples of the “leaving group” for LG¹ to LG³ include a halogen atom(e.g., a fluorine atom, a chlorine atom, a bromine atom, an iodine atometc.), C₁₋₆ alkylsulfonyloxy (e.g., methanesulfonyloxy,ethanesulfonyloxy, trifluoromethanesulfonyloxy etc.), C₁₋₆ alkylsulfonyl(e.g., methanesulfonyl, ethanesulfonyl etc.) and the like. In addition,a substituent capable of converting to a leaving group is encompassed inLG¹-LG³, and it can be converted to a leaving group according to areaction known per se in a desired step. For example, when LG¹-LG³ is amethylsulfanyl group, it is converted to a methanesulfonyl group byoxidation reaction.

The following each step can be performed without solvent, or bydissolving or suspending starting material compound in a suitablesolvent prior to the reaction. In this case, solvent may be used alone,or two or more kinds of these solvents may be mixed in an appropriateratio and used. Specific examples of the solvent used for the productionmethod of the compound of the present invention include the followings.

alcohols: methanol, ethanol, 1-propanol, 2-propanol, tert-butyl alcohol,tert-amyl alcohol, 2-methoxyethanol etc.ethers: diethyl ether, diisopropyl ether, diphenyl ether,tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane etc.aromatic hydrocarbons: benzene, chlorobenzene, toluene, xylene etc.saturated hydrocarbons: cyclohexane, hexane etc. amides:N,N-dimethylformamide, N,N-dimethylacetamide, hexamethylphosphorictriamide, N-methylpyrrolidone etc.halogenated hydrocarbons: dichloromethane, chloroform, carbontetrachloride, 1,2-dichloroethane etc.nitriles: acetonitrile, propionitrile etc.sulfoxides: dimethylsulfoxide etc.organic bases: triethylamine, pyridine, lutidine etc.acid anhydrides: acetic anhydride etc.organic acids: formic acid, acetic acid, propionic acid, trifluoroaceticacid, methanesulfonic acid etc.inorganic acids: hydrochloric acid, sulfuric acid etc.esters: methyl acetate, ethyl acetate, butyl acetate etc.ketones: acetone, methyl ethyl ketone etc.water

Specific examples of the base or acid scavenger used for the productionmethod of the compound of the present invention include the followings.

inorganic bases: sodium hydroxide, potassium hydroxide, magnesiumhydroxide etc.basic salts: sodium carbonate, potassium carbonate, cesium carbonate,calcium carbonate, sodium hydrogen carbonate etc.organic bases: triethylamine, diisopropylethylamine, tributylamine,cyclohexyldimethylamine, pyridine, lutidine, 4-dimethylaminopyridine,N,N-dimethylaniline, N-methylpiperidine, N-methylpyrrolidine,N-methylmorpholine, 1,5-diazabicyclo[4.3.0]-5-nonene,1,4-diazabicyclo[2.2.2]octane, 1,8-diazabicyclo[5.4.0]-7-undecene,imidazole etc.metal alkoxides: sodium methoxide, sodium ethoxide, potassiumtert-butoxide etc.alkali metal hydrides: sodium hydride, potassium hydride etc. metalamides: sodium amide, lithiumdiisopropylamide,lithiumhexamethyldisilazide etc.organic lithium reagents: methyllithium, n-butyllithium,sec-butyllithium, tert-butyllithium etc.

Specific examples of the acid or acid catalyst used for the productionmethod of the compound of the present invention include the followings.

inorganic acids: hydrochloric acid, sulfuric acid, nitric acid,hydrobromic acid, phosphoric acid etc.organic acids: acetic acid, trifluoroacetic acid, oxalic acid, phthalicacid, fumaric acid, tartaric acid, maleic acid, citric acid, succinicacid, methanesulfonic acid, p-toluenesulfonic acid, 10-camphorsulfonicacid etc.Lewis acid: boron trifluoride ether complex, zinc iodide, anhydrousaluminum chloride, anhydrous zinc chloride, anhydrous iron chloride etc.

Compound (I) can be produced according to Production Method A.

Unless otherwise specified, each symbol in the general formulas in theschemes is as defined above. Each R^(a) is a hydrogen atom or anoptionally substituted C₁₋₆ alkyl group. When each R^(a) is anoptionally substituted C₁₋₆ alkyl group, two R^(a) in combinationoptionally form a ring such as 4,4,5,5-tetramethyl-1,3,2-dioxaborolaneand the like. R⁴ is an optionally substituted hydrocarbon group, anoptionally substituted heterocyclic group or a hydrogen atom. X² is anoptionally substituted carbon atom or a nitrogen atom.

X³ is an oxygen atom or a sulfur atom.

Examples of the “optionally substituted C₁₋₆ alkyl group” for R^(a)include those similar to the “optionally substituted C₁₋₆ alkyl group”for R¹.

Examples of the “optionally substituted hydrocarbon group” and the“optionally substituted heterocyclic group” for R⁴ include those similarto the “optionally substituted hydrocarbon group” and “optionallysubstituted heterocyclic group” for R^(A), R^(A)′ or R^(B)′.

Examples of the substituent of the “optionally substituted carbon atom”for X² include those similar to the substituent of the “optionallysubstituted aromatic heterocyclic group” for R².

[Production Method A]

(Step A-1)

Compound (6) can be produced by reacting compound (2) with compound (3),or compound (2) with compound (4), or compound (2) with compound (5).The reaction is carried out using compound (2) and compound (3), orcompound (2) and compound (4), or compound (2) and compound (5) in thepresence of an acid catalyst, a base or a metal catalyst. Examples ofthe acid catalyst include organic acids and the like. The acid catalystis used in an amount of about 0.05 to 2 mol per 1 mol of compound (2).Examples of the base include basic salts, organic bases, alkali metalhydrides, organic lithium reagents and the like. The base is used in anamount of about 1 to 20 mol per 1 mol of compound (2). Examples of themetal catalyst include palladium compounds [e.g.: palladium(II) acetate,tetrakis(triphenylphosphine)palladium(0),dichlorobis(triphenylphosphine)palladium(II),dichlorobis(triethylphosphine)palladium(II),tris(dibenzylideneacetone)dipalladium(0),[1,1-bis(diphenylphosphino)ferrocene]dichloropalladium(II), a complex ofpalladium(II) acetate and 1,1′-bis(diphenylphosphino)ferrocene, and thelike], copper compounds [e.g.: copper(I) iodide, copper(I) bromide andthe like] and the like. The metal catalyst is used in an amount of about0.000001 to 10 mol per 1 mol of compound (2). The metal catalyst can beused together with a phosphine ligand [e.g.: triphenylphosphine,4,5-bis(diphenylphosphino)-9,9-dimethyxanthene, tri-tert-butylphosphine,tri-tert-butylphosphine tetrafluoroborate and the like] or an amineligand [e.g.: 8-methylquinolin-1-ol, 1,10-phenanthroline,1,2-diaminocyclohexane, N,N′-dimethyl-1,2-ethanediamine and the like].The phosphine ligand or amine ligand is used in an amount of about 0.01to 5 mol per 1 mol of compound (2). Compound (3), compound (4) orcompound (5) is used in an amount of about 0.8 to 10 mol per 1 mol ofcompound (2). When the reaction is carried out using a metal catalyst,the reaction is preferably carried out in the presence of a base.Examples of the base include inorganic bases, basic salts and the like.The base is used in an amount of about 1 to 20 mol per 1 mol of compound(2). When the reaction is carried out using a metal catalyst unstable tooxygen, for example, the reaction is preferably carried out under inertgas such as argon gas, nitrogen gas and the like. This reaction isadvantageously carried out in a solvent inert to the reaction. Thesolvent is not particularly limited as long as the reaction proceeds.Preferable examples thereof include alcohols, ethers, aromatichydrocarbons, saturated hydrocarbons, amides, halogenated hydrocarbons,nitriles, esters, sulfoxides, water, mixed solvents thereof and thelike. While the reaction time varies depending on the kind of thereagent and solvent to be used, it is generally 1 min to 200 hr. Thereaction temperature is preferably 0 to 200° C. In addition, microwavemay be irradiated to promote the reaction. Compound (2), compound (3),compound (4) and compound (5) may be a commercially available product,or can also be produced according to a method known per se or a methodanalogous thereto.

(Step A-2)

Compound (I) can be produced by reacting compound (6) with compound (7).The reaction is carried out in the same manner as in the method in StepA-1. Compound (7) may be a commercially available product, or can alsobe produced according to a method known per se or a method analogousthereto.

Compound (6) wherein R² is

can also be produced from compound (8) according to a sequence reactionstep of Step A-3 to Step A-4.

(Step A-3)

Compound (10) can be produced by subjecting compound (8) to condensationwith compound (9). The condensation reaction is carried out by reactingcompound (8) or a reactive derivative thereof with compound (9).Examples of the reactive derivative include acid halides such as acidchlorides, acid bromides and the like; acid amides with pyrazole,imidazole, benzotriazole and the like; mixed anhydride with acetic acid,propionic acid, butyric acid and the like; acid azides; activated esterssuch as diethoxyphosphoric acid ester, diphenoxyphosphoric acid ester,p-nitrophenyl ester, 2,4-dinitrophenyl ester, cyanomethyl ester,pentachlorophenyl ester, an ester with N-hydroxysuccinimide, an esterwith N-hydroxyphthalimide, an ester with 1-hydroxybenzotriazole, anester with 6-chloro-1-hydroxybenzotriazole, an ester with1-hydroxy-1H-2-pyridone, and the like; activated thio esters such as2-pyridylthio ester, 2-benzothiazolylthio ester and the like, and thelike. Alternatively, instead of use of the reactive derivative, compound(8) may be directly reacted with compound (9) in the presence of asuitable condensing agent. Examples of the condensing agent includeN,N′-di-substituted carbodiimides such as N,N′-dicyclohexylcarbodiimide, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (WSC)hydrochloride and the like; azolides such as N,N′-carbonyldiimidazoleand the like; dehydrating agents such asN-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline, phosphorus oxychloride,alkoxy acetylene and the like; 2-halogeno pyridinium salts such as2-chloromethylpyridinium iodide, 2-fluoro-1-methylpyridinium iodide andthe like; phosphorylcyanides such as diethylphosphorylcyanide and thelike;2-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluroniumhexafluorophosphate(HATU),O-(7-azabenzotriazole-1-yl)-N,N,N′,N′-tetramethyluroniumtetrafluoroborate(TATU) and the like. The reaction is considered to proceed via areactive derivative of compound (8) by using a condensing agent.Compound (9) is generally used in an amount of about 0.8 to 5 mol per 1mol of compound (8) or a reactive derivative thereof. This reaction isadvantageously carried out in a solvent inert to the reaction. Thesolvent is not particularly limited as long as the reaction proceeds.Preferable examples thereof include ethers, aromatic hydrocarbons,saturated hydrocarbons, amides, halogenated hydrocarbons, nitriles,sulfoxides, aromatic organic bases, mixed solvent thereof and the like.In addition, when an acidic substance is generated due to the reaction,the reaction can be carried out in the presence of an acid scavenger toremove the acidic substance from the reaction system. Examples of theacid scavenger include basic salts, organic bases and the like. Inaddition, for example, basic salts, organic bases and the like can alsobe used to promote the reaction. While the reaction time variesdepending on the kind of the reagent and solvent to be used, it isgenerally 1 min to 72 hr. The reaction temperature is preferably 0 to100° C. Compound (8) and compound (9) may be a commercially availableproduct, or can also be produced according to a method known per se or amethod analogous thereto.

(Step A-4)

Compound (6) can be produced by treating compound (10) with an acid or adehydrating agent. Examples of the acid include organic acids, inorganicacids and the like. The acid is used in an amount of about 1 to 50 molper 1 mol of compound (10). Examples of the dehydrating agent includephosphorus oxychloride, methyl carbamate-N-(triethylammonium sulfonyl)(Burgess reagent) and the like. The dehydrating agent is used in anamount of about 1 to 10 mol per 1 mol of compound (10). Where desired,the reaction can also be carried out in the presence of a sulfidizingagent. Examples of the sulfidizing agent include2,4-bis(4-methoxyphenyl)-1,3,2,4-dithiadiphosphetane-2,4-disulfide(Lawesson's reagent) and the like. The sulfidizing agent is used in anamount of about 1 to 10 mol per 1 mol of compound (10). This reaction isadvantageously carried out in a solvent inert to the reaction. Thesolvent is not particularly limited as long as the reaction proceeds.Preferable examples thereof include ethers, aromatic hydrocarbons,saturated hydrocarbons, amides, halogenated hydrocarbons, nitriles,sulfoxides, aromatic organic bases, mixed solvent thereof and the like.In addition, when an acidic substance is generated due to the reaction,the reaction can be carried out in the presence of an acid scavenger toremove the acidic substance from the reaction system. Examples of theacid scavenger include basic salts, organic bases and the like. Inaddition, for example, basic salts, organic bases and the like can alsobe used to promote the reaction. While the reaction time variesdepending on the kind of the reagent and solvent to be used, it isgenerally 1 min to 72 hr. The reaction temperature is preferably 0 to150° C.

In compound (I), for example, compound (Ic) can also be produced fromcompound (Ia) according to Production Method B explained below. Inaddition, in compound (I), for example, compound (Ie) can also beproduced from compound (Id) according to Production Method B explainedbelow.

R⁵ and R⁸ are each an optionally substituted hydrocarbon group.

R⁶ and R⁷ are each a hydrogen atom, a C₁₋₁₀ alkyl group, a C₂₋₁₀ alkenylgroup, a C₃₋₁₀ cycloalkyl group, a C₃₋₁₀ cycloalkenyl group, a C₆₋₁₄aryl group, a C₇₋₁₄ aralkyl group, a C₈₋₁₃ arylalkenyl group or aheterocyclic group (e.g., an aromatic heterocyclic group, a non-aromaticheterocyclic group), each of which is optionally substituted, or acylgroup, or R⁶ and R⁷ in combination an optionally form an optionallysubstituted heterocyclic group.

A¹ is an optionally further substituted and optionally bridgedpiperidine ring, and A² is an optionally further substituted andoptionally bridged piperazine ring.

Ring A¹ and Ring A² optionally have 1 to 5 (preferably 1 to 3)substituents at substitutable position(s). Examples of the substituentinclude substituents selected from the above-mentioned Substituent GroupB. When the number of the substituents is plural, the respectivesubstituents may be the same or different.

Examples of the “bridged piperidine ring and bridged piperazine ring”include 8-azabicyclo[3.2.1]octane, 2,5-diazabicyclo[2.2.1]heptane,3-azabicyclo[3.1.0]hexane and the like.

Examples of the “optionally substituted hydrocarbon group” for R⁵ or R⁸include those similar to the “optionally substituted hydrocarbon group”for R^(A), R^(A)′ or R^(B)′.

Examples of the “optionally substituted hydrocarbon group” and“optionally substituted heterocyclic group” for R⁶ or R⁷ include thosesimilar to the “optionally substituted hydrocarbon group” and“optionally substituted heterocyclic group” for R^(A), R^(A)′ or R^(B)′.

Examples of the “optionally substituted heterocyclic group” formed by R⁶and R⁷ in combination include those similar to the “optionallysubstituted heterocyclic group” for R^(A), R^(A)′ or R^(B)′.

[Production Method B]

(Step B-1)

Compound (Ib) can be produced by subjecting compound (Ia) to hydrolysis.The hydrolysis reaction can be carried out using an inorganic base or aninorganic acid, under a reaction condition generally used for ahydrolysis reaction. It can be carried out according to a method knownper se, for example, the method described in “Protective Groups inOrganic Synthesis, 3rd Ed”, Wiley-Interscience (1999) (Theodora W.Greene, Peter G. M. Wuts), or the like.

(Step B-2)

Compound (Ic) can be produced by subjecting compound (Ib) tocondensation with compound (11). The reaction is carried out in the samemanner as in the method in Step A-3. Compound (11) may be a commerciallyavailable product, or can also be produced according to a method knownper se or a method analogous thereto.

(Step B-3)

Compound (12) can be produced by removing the carbamate group ofcompound (Id). The removal of the carbamate group can be carried outaccording to a method known per se, for example, the method described in“Protective Groups in Organic Synthesis, 3rd Ed”, Wiley-Interscience(1999) (Theodora W. Greene, Peter G. M. Wuts), or the like.

(Step B-4)

Compound (Ie) can be produced by subjecting compound (12) tocondensation with compound (11) (R¹═N(R⁶)(R⁷)) or compound (13).

When compound (12) is condensed with compound (13), the reaction iscarried out in the same manner as in the method in Step A-3.

When compound (12) is condensed with compound (11), the reaction iscarried out by reacting the reactive derivative of compound (12) withcompound (11), by directly reacting compound (12) with compound (11) inthe presence of a suitable condensing agent, or the like. Examples ofthe reactive derivative include carboxamide with imidazole and the like,and the like. Examples of the condensing agent include phosgenes such asphosgene, triphosgene and the like, azolides such asN,N′-carbonyldiimidazole and the like, and the like. The reaction isconsidered to proceed via a reactive derivative of compound (12) byusing a condensing agent. Compound (11) is generally used in an amountof about 0.8 to 5 mol per 1 mol of compound (12) or a reactivederivative thereof. This reaction is advantageously carried out in asolvent inert to the reaction. The solvent is not particularly limitedas long as the reaction proceeds. Preferable examples thereof includeethers, aromatic hydrocarbons, saturated hydrocarbons, amides,halogenated hydrocarbons, nitriles, sulfoxides, aromatic organic bases,mixed solvent thereof and the like. In addition, when an acidicsubstance is generated due to the reaction, the reaction can be carriedout in the presence of an acid scavenger to remove the acidic substancefrom the reaction system. Examples of the acid scavenger include basicsalts, organic bases and the like. In addition, for example, basicsalts, organic bases and the like can also be used to promote thereaction. While the reaction time varies depending on the kind of thereagent and solvent to be used, it is generally 1 min to 72 hr. Thereaction temperature is preferably 0 to 100° C. Compound (13) may be acommercially available product, or can also be produced according to amethod known per se or a method analogous thereto.

The starting compound and/or the production intermediate for thecompound (I) may form a salt. While the salt is not particularly limitedas long as the reaction can be performed, examples thereof include thosesimilar to the salts optionally formed by the compound (I) and the like,and the like.

As for the configuration isomers (E, Z forms) of compound (I), they canbe isolated and purified when isomerization occurs, for example,according to a conventional separation means such as extraction,recrystallization, distillation, chromatography and the like to obtain apure compound. In addition, the corresponding pure isomer can beobtained by isomerizing a double bond using heating, an acid catalyst, atransition metal complex, a metal catalyst, a radical catalyst, lightirradiation or a strong base catalyst and the like, according to themethod described in Jikken Kagaku Kouza (Courses in ExperimentalChemistry) 14 (The Chemical Society of Japan ed.), pages 251 to 253, 4thEdition Jikken Kagaku Kouza 19 (The Chemical Society of Japan ed.),pages 273 to 274 or a method analogous thereto.

Compound (I) contains a stereoisomer depending to the kind of asubstituent, and each stereoisomer and a mixture thereof are encompassedin the present invention.

Compound (I) may be a hydrate or a non-hydrate.

When desired, compound (I) can be synthesized by performing deprotectionreaction, acylation reaction, alkylation reaction, hydrogenationreaction, oxidation reaction, reduction reaction, reaction of carbonchain extension, substituent exchange reaction singly or two or morethereof in combination.

When the objective product is obtained as a free form by theabove-mentioned reaction, it can be converted to a salt according to aconventional method, or when the objective product is obtained as asalt, it can be converted to a free form or other salt according to aconventional method. The thus-obtained compound (I) can also be isolatedand purified from a reaction mixture according to a known method such asphase transfer, concentration, solvent extraction, distillation,crystallization, recrystallization, chromatography and the like.

When compound (I) contains a configurational isomer, a diastereomer, aconformer and the like, each can be isolated according to theabove-mentioned separation and purification methods, if desired. Inaddition, when compound (I) is racemic, d-form and 1-form can beisolated according to a conventional optical resolution.

In each of the above-mentioned reactions, when the compound has afunctional group such as an amino group, a hydroxy group or a carboxylgroup, the reaction can be carried out after a protecting groupgenerally used in peptide chemistry and the like is introduced intothese groups. By removing the protecting group as necessary after thereaction, the objective compound can be obtained.

Examples of the protecting group include formyl, C₁₋₆ alkyl-carbonyl(e.g., acetyl, propionyl etc.), phenylcarbonyl, C₁₋₆ alkoxy-carbonyl(e.g., methoxycarbonyl, ethoxycarbonyl etc.), phenyloxycarbonyl, C₇₋₁₀aralkyloxy-carbonyl (e.g., benzyloxycarbonyl etc.), trityl, phthaloyland the like, each of which is optionally substituted. Examples of thesubstituent include a halogen atom (e.g., fluorine, chlorine, bromine,iodine etc.), C₁₋₆ alkyl-carbonyl (e.g., acetyl, propionyl, valeryletc.), nitro and the like. The number of substituents is, for example, 1to 3.

The removal method of the protecting group can be carried out accordingto a method known per se, and for example, a method using acid, base,ultraviolet rays, hydrazine, phenylhydrazine, sodiumN-methyldithiocarbamate, tetrabutylammonium fluoride, palladium acetateand the like, a reduction method, and the like can be employed.

The thus-obtained compound (I), other reaction intermediate therefor andstarting compounds thereof can be isolated and purified from a reactionmixture according to a method known per se, for example, extraction,concentration, neutralization, filtration, distillation,recrystallization, column chromatography, thin layer chromatography,preparative high performance liquid chromatography (preparative HPLC),moderate-pressure preparative liquid chromatography (moderate-pressurepreparative LC) and the like.

A salt of compound (I) can be produced according to a method known perse. For example, when compound (I) is a basic compound, it can beproduced by adding an inorganic acid or organic acid, or when compound(I) is an acidic compound, by adding an organic base or inorganic base.

When compound (I) contains an optical isomer, each optical isomer and amixture thereof are encompassed in the scope of the present invention,and these isomers can be subjected to optical resolution or can beproduced respectively, according to a method known per se, if desired.

When compound (I) contains a configurational isomer, a diastereomer, aconformer and the like, each can be isolated according to theabove-mentioned separation and purification methods, if desired. Inaddition, when compound (I) is racemic, S-form and R-form can beisolated according to a conventional optical resolution.

When compound (I) contains a stereoisomer, each isomer and a mixturethereof are encompassed in the present invention.

Compound (I) may be a prodrug, and the prodrug of compound (I) refers toa compound which is converted to compound (I) as a result of a reactionwith an enzyme, gastric acid, etc. under physiological conditions invivo, thus a compound that undergoes enzymatic oxidation, reduction,hydrolysis etc. to convert to compound (I) and a compound that undergoeshydrolysis and the like by gastric acid, etc. to convert to compound(I).

Examples of the prodrug for compound (I) include

(1) a compound obtained by subjecting an amino group in compound (I) toacylation, alkylation or phosphorylation (e.g., a compound obtained bysubjecting an amino group in compound (I) to eicosanoylation,alanylation, pentylaminocarbonylation,(5-methyl-2-oxo-1,3-dioxolen-4-yl)methoxycarbonylation,tetrahydrofurylation, pyrrolidylmethylation, pivaloyloxymethylation,tert-butylation, ethoxycarbonylation, tert-butoxycarbonylation,acetylation, cyclopropylcarbonylation and the like);(2) a compound obtained by subjecting a hydroxy group in compound (I) toacylation, alkylation, phosphorylation or boration (e.g., a compoundobtained by subjecting a hydroxy group in compound (I) to acetylation,palmitoylation, propanoylation, pivaloylation, succinylation,fumarylation, alanylation or dimethylaminomethylcarbonylation and thelike);(3) a compound obtained by subjecting a carboxyl group in compound (I)to esterification or amidation (e.g., a compound obtained by subjectinga carboxyl group in compound (I) to ethyl esterification, phenylesterification, carboxymethyl esterification, dimethylaminomethylesterification, pivaloyloxymethyl esterification, ethoxycarbonyloxyethylesterification, phthalidyl esterification,(5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl esterification,cyclohexyloxycarbonylethyl esterification or methylamidation and thelike) and the like. Any of these compounds can be produced from compound(I) according to a method known per se.

A prodrug of compound (I) may also be one which is converted to compound(I) under physiological conditions as described in “IYAKUHIN no KAIHATSU(Development of Pharmaceuticals)”, Vol. 7, Design of Molecules, p.163-198, Published by HIROKAWA SHOTEN (1990).

In the present specification, compound (I) and a prodrug thereof aresometimes collectively abbreviated as “the compound of the presentinvention”.

When compound (I) has isomers such as optical isomer, stereoisomer,positional isomer, rotamer and the like, such isomers and a mixturethereof are also encompassed in compound (I). For example, when compound(I) has optical isomers, an optical isomer resolved from this compoundis also encompassed in compound (I). These isomers can be obtained as asingle product according to synthesis methods or separation methodsknown per se (e.g., concentration, solvent extraction, columnchromatography, recrystallization, etc.).

Compound (I) may be a crystal, and a single crystal form and a mixtureof crystal forms are both encompassed in compound (I). The crystal canbe produced by crystallizing according to a crystallization method knownper se.

Compound (I) may be a hydrate, a non-hydrate, a solvate or anon-solvate.

Compound (I) may be labeled with an isotope (e.g., ³H, ¹¹C, ¹⁴C, ¹⁸F,³⁵S, ¹²⁵I etc.) and the like.

Compound (I) also encompasses a deuterium conversion form wherein ¹H isconverted to ²H(D).

Compound (I) may be a pharmaceutically acceptable cocrystal or a saltthereof. The cocrystal or a salt thereof means a crystalline substanceconstituted with two or more special solids at room temperature, eachhaving different physical properties (e.g., structure, melting point,melting heat, hygroscopicity, solubility and stability etc.). Thecocrystal or a salt thereof can be produced according to acocrystallization a method known per se.

Compound (I) may also be used as a PET tracer.

The compound of the present invention has low toxicity, and can be usedas it is or in the form of a pharmaceutical composition by mixing with apharmacologically acceptable carrier etc. to mammals (e.g., human,mouse, rat, rabbit, dog, cat, bovine, horse, swine, monkey) as an agentfor the prophylaxis or treatment of various diseases mentioned below.

As pharmacologically acceptable carriers, various organic or inorganiccarrier substances conventionally used as preparation materials can beused. These are incorporated as excipient, lubricant, binder anddisintegrant for solid preparations, or solvent, solubilizing agent,suspending agent, isotonicity agent, buffer and soothing agent forliquid preparations, and the like, and preparation additives such aspreservative, antioxidant, colorant, sweetening agent and the like canbe added as necessary.

Preferable examples of the excipient include lactose, sucrose,D-mannitol, D-sorbitol, starch, gelatinated starch, dextrin, crystallinecellulose, low-substituted hydroxypropylcellulose, sodiumcarboxymethylcellulose, gum arabic, pullulan, light anhydrous silicicacid, synthesis aluminum silicate and magnesium alumino metasilicate.

Preferable examples of the lubricant include magnesium stearate, calciumstearate, talc and colloidal silica.

Preferable examples of the binder include gelatinated starch, sucrose,gelatin, gum arabic, methylcellulose, carboxymethylcellulose, sodiumcarboxymethylcellulose, crystalline cellulose, sucrose, D-mannitol,trehalose, dextrin, pullulan, hydroxypropylcellulose,hydroxypropylmethylcellulose and polyvinylpyrrolidone.

Preferable examples of the disintegrant include lactose, sucrose,starch, carboxymethylcellulose, calcium carboxymethylcellulose,croscarmellose sodium, sodium carboxymethyl starch, light anhydroussilicic acid and low-substituted hydroxypropylcellulose.

Preferable examples of the solvent include water for injection,physiological brine, Ringer's solution, alcohol, propylene glycol,polyethylene glycol, sesame oil, corn oil, olive oil and cottonseed oil.

Preferable examples of the solubilizing agents include polyethyleneglycol, propylene glycol, D-mannitol, trehalose, benzyl benzoate,ethanol, trisaminomethane, cholesterol, triethanolamine, sodiumcarbonate, sodium citrate, sodium salicylate and sodium acetate.

Preferable examples of the suspending agent include surfactants such asstearyltriethanolamine, sodium lauryl sulfate, lauryl aminopropionate,lecithin, benzalkonium chloride, benzethonium chloride, glycerolmonostearate and the like; hydrophilic polymers such as polyvinylalcohol, polyvinylpyrrolidone, sodium carboxymethylcellulose,methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose,hydroxypropylcellulose and the like; polysorbates, and polyoxyethylenehydrogenated castor oil.

Preferable examples of the isotonicity agent include sodium chloride,glycerol, D-mannitol, D-sorbitol and glucose.

Preferable examples of the buffer include buffers such as phosphate,acetate, carbonate, citrate and the like.

Preferable examples of the soothing agent include benzyl alcohol.

Preferable examples of the preservative include p-oxybenzoates,chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid andsorbic acid.

Preferable examples of the antioxidant include sulfite and ascorbate.

Preferable examples of the colorant include aqueous water-soluble foodtar colors (e.g., food colors such as Food Color Red Nos. 2 and 3, FoodColor Yellow Nos. 4 and 5, Food Color Blue Nos. 1 and 2 and the like),water insoluble lake dyes (e.g., aluminum salt of the above-mentionedwater-soluble food tar color) and natural dyes (e.g., β-carotene,chlorophyll, ferric oxide red).

Preferable examples of the sweetening agent include saccharin sodium,dipotassium glycyrrhizinate, aspartame and stevia.

Examples of the dosage form of the pharmaceutical composition includeoral preparations such as tablet (including sugar-coated tablet,film-coated tablet, sublingual tablet, orally disintegrating tablet),capsules (including soft capsule, microcapsule), granule, powder,troche, syrup, emulsion, suspension, films (e.g., orally disintegrablefilms) and the like; and parenteral agents such as injection (e.g.,subcutaneous injection, intravenous injection, intramuscular injection,intraperitoneal injection, drip infusion), external preparations (e.g.,dermal preparation, ointment), suppository (e.g., rectal suppository,vaginal suppository), pellet, nasal preparation, pulmonary preparation(inhalant), eye drop and the like.

These can be respectively safely administered orally or parenterally(e.g., topically, rectally, intravenously administered).

These preparations may be a release control preparation (e.g.,sustained-release microcapsule) such as an immediate-releasepreparation, a sustained-release preparation and the like.

The pharmaceutical composition can be produced according to a methodconventionally used in the field of pharmaceutical formulation, forexample, the method described in the Japanese Pharmacopoeia, and thelike.

While the content of the compound of the present invention in thepharmaceutical composition varies depending on the dosage form, dose ofthe compound of the present invention and the like, it is for example,about 0.1 to 100 wt %.

During production of an oral preparation, coating may be applied asnecessary for the purpose of masking of taste, enteric property ordurability.

Examples of the coating base to be used for coating include sugarcoating base, water-soluble film coating base, enteric film coating baseand sustained-release film coating base.

As the sugar coating base, sucrose is used. Moreover, one or more kindsselected from talc, precipitated calcium carbonate, gelatin, gum arabic,pullulan, carnauba wax and the like may be used in combination.

Examples of the water-soluble film coating base include cellulosepolymers such as hydroxypropyl cellulose, hydroxypropylmethyl cellulose,hydroxyethyl cellulose, methylhydroxyethyl cellulose etc.; syntheticpolymers such as polyvinylacetal diethylaminoacetate, aminoalkylmethacrylate copolymer E [Eudragit E (trade name)], polyvinylpyrrolidoneetc.; and polysaccharides such as pullulan etc.

Examples of the enteric film coating base include cellulose polymerssuch as hydroxypropylmethyl cellulose phthalate, hydroxypropylmethylcellulose acetate succinate, carboxymethylethyl cellulose, celluloseacetate phthalate etc.; acrylic polymers such as methacrylic acidcopolymer L [Eudragit L (trade name)], methacrylic acid copolymer LD[Eudragit L-30D55 (trade name)], methacrylic acid copolymer S [EudragitS (trade name)] etc.; and naturally occurring substances such as shellacetc.

Examples of the sustained-release film coating base include cellulosepolymers such as ethyl cellulose etc.; and acrylic polymers such asaminoalkyl methacrylate copolymer RS [Eudragit RS (trade name)], ethylacrylate-methyl methacrylate copolymer suspension [Eudragit NE (tradename)] etc.

The above-mentioned coating bases may be used after mixing with two ormore kinds thereof at appropriate ratios. For coating, for example, alight shielding agent such as titanium oxide, red ferric oxide and thelike can be used.

The compound of the present invention shows low toxicity (e.g., acutetoxicity, chronic toxicity, genetic toxicity, reproductive toxicity,cardiotoxicity, carcinogenicity) and a few side effects. Therefore, itcan be used as an agent for the prophylaxis or treatment or a diagnosticof various diseases in a mammal (e.g., human, bovine, horse, dog, cat,monkey, mouse, rat).

The compound of the present invention has a superior CH24H inhibitoryaction and can suppress nerve cell death, Aβ increase, intracerebralinflammation and the like.

Accordingly, the compound of the present invention is useful for theprophylaxis, improvement of symptoms, suppression of progression ortreatment of diseases involving enhanced function of CH24H, for example,neurodegenerative disease.

In the present specification, the “neurodegenerative disease” means adisease associated with denaturation of neural tissues.

Specific examples of the neurodegenerative disease include Alzheimer'sdisease, mild cognitive impairment, Huntington's disease, Parkinson'sdisease, multiple sclerosis, amyotrophic lateral sclerosis, traumaticbrain injury, cerebral infarction, glaucoma and the like.

In addition, the compound of the present invention is useful for theprophylaxis, improvement of symptoms, suppression of progression ortreatment of diseases involving enhanced function of CH24H, for example,epilepsy, schizophrenia, spasm and the like.

The dose of the compound of the present invention varies depending onthe administration subject, route of administration, target disease,symptoms, etc. For example, when it is administered orally to an adultpatient (body weight 60 kg), its dose is about 0.01 to 100 mg/kg bodyweight per dose, preferably 0.05 to 30 mg/kg body weight per dose, morepreferably 0.1 to 10 mg/kg body weight per dose and this amount isdesirably administered in 1 to 3 portions daily.

When the compound of the present invention is applied to each of theabove-mentioned diseases, it can be used in an appropriate combinationwith a medicament or a treatment method generally employed for thedisease.

Examples of the medicament (hereinafter to be abbreviated as“concomitant drug”) to be used in combination with the compound of thepresent invention include acetylcholine esterase inhibitors (e.g.,donepezil, rivastigmine, galanthamine, zanapezil etc.), antidementiaagents (e.g., memantine), inhibitors of β amyloid protein production,secretion, accumulation, coagulation and/or deposition, β secretaseinhibitors (e.g.,6-(4-biphenyl)methoxy-2-[2-(N,N-dimethylamino)ethyl]tetralin,6-(4-biphenyl)methoxy-2-(N,N-dimethylamino)methyltetralin,6-(4-biphenyl)methoxy-2-(N,N-dipropylamino)methyltetralin,2-(N,N-dimethylamino)methyl-6-(4′-methoxybiphenyl-4-yl)methoxytetralin,6-(4-biphenyl)methoxy-2-[2-(N,N-diethylamino)ethyl]tetralin,2-[2-(N,N-dimethylamino)ethyl]-6-(4′-methylbiphenyl-4-yl)methoxytetralin,2-[2-(N,N-dimethylamino)ethyl]-6-(4′-methoxybiphenyl-4-yl)methoxytetralin,6-(2′,4′-dimethoxybiphenyl-4-yl)methoxy-2-[2-(N,N-dimethylamino)ethyl]tetralin,6-[4-(1,3-benzodioxol-5-yl)phenyl]methoxy-2-[2-(N,N-dimethylamino)ethyl]tetralin,6-(3′,4′-dimethoxybiphenyl-4-yl)methoxy-2-[2-(N,N-dimethylamino)ethyl]tetralin,an optically active form thereof, a salt thereof and a hydrate thereof,OM99-2 (WO01/00663)), γ secretase inhibitory agent, β amyloid proteincoagulation inhibitory agent (e.g., PTI-00703, ALZHEMED (NC-531),PPI-368 (JP-A-11-514333), PPI-558 (JP-A-2001-500852), SKF-74652(Biochem. J. (1999), 340(1), 283-289)), β amyloid vaccine, β amyloiddegrading enzyme and the like, cerebral function activators (e.g.,aniracetam, nicergoline), other therapeutic drug for Parkinson's disease[(e.g., dopamine receptor agonists (e.g., L-DOPA, bromocriptine,pergolide, talipexole, pramipexole, cabergoline, amantadine), amonoamine oxidase (MAO) inhibitors (e.g., deprenyl, Selgiline(selegiline), ramacemide, riluzole), anticholinergic agents (e.g.,trihexyphenidyl, biperiden), COMT inhibitors (e.g., entacapone)],therapeutic drug for amyotropic lateral sclerosis (e.g., riluzole etc.,neurotrophic factor), therapeutic drug for abnormal behavior wanderingand the like due to the progress of dementia (e.g., sedative drug,antianxiety drug), apoptosis inhibitors (e.g., CPI-1189, IDN-6556,CEP-1347), neuronal differentiation or regeneration promoters (e.g.,leteprinim, xaliproden (SR-57746-A), SB-216763, Y-128, VX-853,prosaptide,5,6-dimethoxy-2-[2,2,4,6,7-pentamethyl-3-(4-methylphenyl)-2,3-dihydro-1-benzofuran-5-yl]isoindoline,5,6-dimethoxy-2-[3-(4-isopropylphenyl)-2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-yl]isoindoline,6-[3-(4-isopropylphenyl)-2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-yl]-6,7-dihydro-5H-[1,3]dioxolo[4,5-f]isoindoleand optically active forms, salts and hydrates thereof), antidepressants(e.g., desipramine, amitriptyline, imipramine, tramadol), antiepilepsydrug (e.g., lamotrigine), antianxiety drugs (e.g., benzodiazepine),non-steroidal anti-inflammatory drugs (e.g., meloxicam, tenoxicam,indomethacin, ibuprofen, celecoxib, rofecoxib, aspirin, indomethacin),disease-modifying anti-rheumatic drugs (DMARDs), anti-cytokine drugs(e.g., TNF inhibitor MAP kinase inhibitor), steroidal drugs (e.g.,dexamethasone, hexestrol, cortisone acetate), therapeutic agents forincontinence or frequent urination (e.g., flavoxate hydrochloride,oxybutynin hydrochloride, propiverine hydrochloride), phosphodiesteraseinhibitors (e.g., sildenafil (citrate)), dopamine agonists (e.g.,apomorphine etc.), antiarrhythmics (e.g., mexiletine), sex hormones orderivatives thereof (e.g., progesterone, estradiol, estradiol benzoate),therapeutic agents for osteoporosis (e.g., alfacalcidol, calcitriol,elcatonin, calcitonin salmon, estriol, ipriflavone, disodiumpamidronate, sodium alendronate hydrate, disodium incadronate),parathyroid hormone (PTH), calcium receptor antagonists, therapeuticdrugs for insomnia (e.g., benzodiazepine medicament, non-benzodiazepinemedicament, melatonin agonist), therapeutic drugs for schizophrenia(e.g., typical antipsychotic agents such as haloperidol and the like;atypical antipsychotic agents such as clozapine, olanzapine,risperidone, aripiprazole and the like; medicament acted on metabotropicglutamate receptor or ionic channel-conjugated glutamate receptor;phosphodiesterase inhibitor) and the like.

In addition, a combined use with a transplantation method of neural stemcell or neural precursor cell prepared from embryonic stem cell ornervous tissue, or fetal neural tissue, and a combined use with apharmaceutical agent such as an immunosuppressant after thetransplantation and the like.

Furthermore, the compound of the present invention may be used incombination with the following concomitant drugs.

(1) Therapeutic Agent for Diabetes

For example, insulin preparations (e.g., animal insulin preparationextracted from the pancreas of bovine, swine; human insulin preparationgenetically synthesized using Escherichia coli, yeast; zinc insulin;protamine zinc insulin; insulin fragment or derivatives (e.g., INS-1),oral insulin preparation), insulin sensitizer (e.g., pioglitazone or asalt thereof (preferably hydrochloride), rosiglitazone or a salt thereof(preferably maleate), Tesaglitazar, Ragaglitazar, Muraglitazar,Edaglitazone, Metaglidasen, Naveglitazar, AMG-131, THR-0921),α-glucosidase inhibitor (e.g., voglibose, acarbose, miglitol,emiglitate), biguanide (e.g., metformin, buformin or a salt thereof(e.g., hydrochloride, fumarate, succinate)), insulin secretagogue[sulfonylurea (e.g., tolbutamide, glibenclamide, gliclazide,chlorpropamide, tolazamide, acetohexamide, glyclopyramide, glimepiride,glipizide, glybuzole), repaglinide, nateglinide, mitiglinide or calciumsalt hydrate thereof, glucose-dependent insulin secretagogue (e.g.,[(3S)-6-({2′,6′-dimethyl-4′-[3-(methylsulfonyl)propoxy]biphenyl-3-yl}methoxy)-2,3-dihydro-1-benzofuran-3-yl]aceticacid or a salt thereof)], dipeptidyl peptidase IV inhibitor (e.g.,Alogliptin, Vildagliptin, Sitagliptin, Saxagliptin, T-6666, TS-021), β3agonist (e.g., AJ-9677), GPR40 agonist, GLP-1 receptor agonist [e.g.,GLP-1, GLP-1MR agent, NN-2211, AC-2993 (exendin-4), BIM-51077,Aib(8,35)hGLP-1(7,37)NH₂, CJC-1131], amylin agonist (e.g., pramlintide),phosphotyrosine phosphatase inhibitors (e.g., sodium vanadate),gluconeogenesis inhibitor (e.g., glycogen phosphorylase inhibitorglucose-6-phosphatase inhibitors, glucagon antagonists), SGLUT(sodium-glucose cotransporter) inhibitor (e.g., T-1095),11β-hydroxysteroid dehydrogenase inhibitor (e.g., BVT-3498), adiponectinor an agonist thereof, IKK inhibitor (e.g., AS-2868), leptin resistanceimproving drugs, somatostatin receptor agonists, glucokinase activators(e.g., Ro-28-1675), GIP (Glucose-dependent insulinotropic peptide) andthe like.

(2) Therapeutic Agents for Diabetic Complications

For example, aldose reductase inhibitors (e.g., tolrestat, epalrestat,zenarestat, zopolrestat, minalrestat, fidarestat, CT-112), neurotrophicfactor and an increasing agent thereof (e.g., NGF, NT-3, BDNF,neurotrophic factors and increasing drugs described in WO01/14372 (e.g.,4-(4-chlorophenyl)-2-(2-methyl-1-imidazolyl)-5-[3-(2-methylphenoxy)propyl]oxazole)),nerve regeneration promoting agent (e.g., Y-128), PKC inhibitor (e.g.,ruboxistaurin mesylate), AGE inhibitor (e.g., ALT946, pimagedine,pyratoxanthine, N-phenacylthiazolium bromide (ALT766), ALT-711, EXO-226,Pyridorin, pyridoxamine), active oxygen scavengers (e.g., thiocticacid), cerebral vasodilator (e.g., tiapuride, mexiletine), somatostatinreceptor agonists (e.g., BIM23190), apoptosis signal regulating kinase-1(ASK-1) inhibitor and the like can be mentioned.

(3) Therapeutic Agent for Hyperlipidemia

For example, statin compound (e.g., pravastatin, simvastatin,lovastatin, atorvastatin, fluvastatin, rosuvastatin, pitavastatin, or asalt thereof (e.g., sodium salt, calcium salt)), squalene synthaseinhibitors (e.g., lapaquistat acetate or a salt thereof), fibratecompound (e.g., bezafibrate, clofibrate, simfibrate, clinofibrate), ACATinhibitor (e.g., Avasimibe, Eflucimibe), anion exchange resin (e.g.,colestyramine), probucol, nicotinic acid drug (e.g., nicomol,niceritrol), ethyl icosapentate, phytosterol (e.g., soysterol, gammaoryzanol) and the like.

(4) Antihypertensive Agent

For example, angiotensin converting enzyme inhibitor (e.g., captopril,enalapril, delapril), angiotensin II antagonist (e.g., candesartancilexetil, losartan, eprosartan, valsartan, telmisartan, irbesartan,tasosartan,1-[[2′-(2,5-dihydro-5-oxo-4H-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl]-2-ethoxy-1H-benzimidazole-7-carboxylicacid, Azilsartan, Azilsartan medoxomil), calcium antagonist (e.g.,manidipine, nifedipine, amlodipine, efonidipine, nicardipine), potassiumchannel opener (e.g., levcromakalim, L-27152, AL 0671, NIP-121),clonidine and the like.

(5) Antiobesity Agent

For example, central-acting antiobesity agent (e.g., dexfenfluramine,fenfluramine, phentermine, sibutramine, amfepramone, dexamphetamine,mazindol, phenylpropanolamine, clobenzorex; MCH receptor antagonists(e.g., SB-568849; SNAP-7941; compounds described in WO01/82925 andWO01/87834); neuropeptide Y antagonist (e.g., CP-422935); cannabinoidreceptor antagonists (e.g., SR-141716, SR-147778); ghrelin antagonist;11β-hydroxysteroid dehydrogenase inhibitor (e.g., BVT-3498)), pancreaticlipase inhibitors (e.g., orlistat, cetilistat), β3 agonist (e.g.,AJ-9677, AZ40140), anorectic peptides (e.g., leptin, CNTF (ciliaryneurotrophic factor)), cholecystokinin agonist (e.g., lintitript,FPL-15849), anorexigenic agent (e.g., P-57) and the like.

(6) Diuretic

For example, xanthine derivative (e.g., theobromine sodium salicylate,theobromine calcium salicylate), thiazide preparation (e.g., ethiazide,cyclopenthiazide, trichloromethyazide, hydrochlorothiazide,hydroflumethiazide, benzylhydrochlorothiazide, penflutizide,polythiazide, methyclothiazide), antialdosterone preparation (e.g.,spironolactone, triamterene), carbonic anhydrase inhibitors (e.g.,acetazolamide), chlorobenzenesulfonamide agent (e.g., chlortalidone,mefruside, indapamide), azosemide, isosorbide, ethacrynic acid,piretanide, bumetanide, furosemide and the like.

(7) Chemotherapeutic Agent

For example, alkylating agents (e.g., cyclophosphamide, ifosfamide),metabolic antagonists (e.g., methotrexate, 5-fluorouracil or derivativethereof), antitumor antibiotics (e.g., mitomycin, adriamycin),plant-derived antitumor agents (e.g., vincristine, vindesine, Taxol),cisplatin, carboplatin, etoposide and the like. Of these, Furtulon andNeoFurtulon, which are 5-fluorouracil derivatives, and the like arepreferable.

(8) Immunotherapeutic Agent

For example, microorganism or bacterial components (e.g., muramyldipeptide derivative, Picibanil), polysaccharides having immunitypotentiating activity (e.g., lentinan, schizophyllan, krestin),cytokines obtained by genetic engineering techniques (e.g., interferon,interleukin (IL)), colony stimulating factors (e.g., granulocyte colonystimulating factor erythropoietin) and the like, with preference givento interleukins such as IL-1, IL-2, IL-12 and the like.

(9) Antithrombotic Agent

For example, heparin (e.g., heparin sodium, heparin calcium, dalteparinsodium), warfarin (e.g., warfarin potassium), anti-thrombin drug (e.g.,argatroban), thrombolytic agent (e.g., urokinase, tisokinase, alteplase,nateplase, monteplase, pamiteplase), platelet aggregation inhibitor(e.g., ticlopidine hydrochloride, cilostazol, ethyl icosapentate,beraprost sodium, sarpogrelate hydrochloride) and the like.

(10) Cachexia Improving Medicament

For example, cyclooxygenase inhibitors (e.g., indomethacin etc.) [CancerResearch, Vol. 49, pages 5935-5939, 1989], progesterone derivatives(e.g., megestrol acetate) [Journal of Clinical Oncology, Vol. 12, pages213-225, 1994], glucosteroids (e.g., dexamethasone etc.), metoclopramideagents, tetrahydrocannabinol agents (publications are all as mentionedabove), fat metabolism improving agents (e.g., eicosapentaenoic acidetc.) [British Journal of Cancer, Vol. 68, pages 314-318, 1993], growthhormones, IGF-1, or antibodies to a cachexia-inducing factor such asTNF-α, LIF, IL-6, oncostatin M and the like.

Two or more kinds of the above-mentioned concomitant drugs may be usedin combination at an appropriate ratio.

It is also possible to apply compound of the present invention to eachof the above-mentioned diseases in combination with a biologic (e.g.,antibody, vaccine preparation etc.), or as a combination therapy incombination with gene therapy method and the like.

Examples of the antibody and vaccine preparation include vaccinepreparation to angiotensin II, vaccine preparation to CETP, CETPantibody, TNFα antibody and antibody to other cytokine, amyloid βvaccine preparation, type 1 diabetes vaccine (e.g., DIAPEP-277manufactured by Peptor Ltd.), anti-HIV antibody, HIV vaccine preparationand the like, antibody or vaccine preparation to cytokine,renin-angiotensin enzyme and a product thereof, antibody or vaccinepreparation to enzyme or protein involved in blood lipid metabolism,antibody or vaccine to enzyme or protein involved in blood coagulationor fibrinolytic system, antibody or vaccine preparation to proteininvolved in saccharometabolism or insulin resistance and the like.

In addition, a combined use with a biological preparation involved in agrowth factor such as GH, IGF and the like is possible.

Examples of the gene therapy method include a treatment method using agene relating to cytokine, renin-angiotensin enzyme and a productthereof, G protein, G protein conjugated receptor and itsphosphorylation enzyme, a treatment method using a DNA decoy such asNFκB decoy and the like, a treatment method using an antisense, atreatment method using a gene relating to an enzyme or protein involvedin blood lipid metabolism (e.g., gene relating to metabolism, excretionor absorption of cholesterol or triglyceride or HDL-cholesterol or bloodphospholipid), a treatment method using a gene relating to an enzyme orprotein involved in angiogenesis therapy targeting obstruction ofperipheral vessel and the like (e.g., growth factors such as HGF, VEGFetc.), a treatment method using a gene relating to a protein involved insaccharometabolism or insulin resistance, an antisense to cytokine suchas TNF and the like, and the like.

In addition, it is possible to use in combination with various organregeneration methods such as heart regeneration, kidney regeneration,pancreas regeneration, blood vessel regeneration and the like or celltransplantation therapy utilizing bone marrow cell (myelomonocytic cell,myeloid stem cell) or an artificial organ utilizing tissue engineering(e.g., artificial blood vessel and cardiac muscle cell sheet).

The time of administration of the compound of the present invention andthat of the concomitant drug are not limited, and they may beadministered simultaneously or in a staggered manner to theadministration subject. Furthermore, the compound of the presentinvention and the concomitant drug may be administered as two kinds ofpreparations containing each active ingredient, or a single preparationcontaining both active ingredients.

The dose of the concomitant drug can be appropriately determined basedon the dose employed in clinical situations. The mixing ratio of thecompound of the present invention and a concomitant drug can beappropriately determined depending on the administration subject,administration route, target disease, symptom, combination and the like.When the subject of administration is human, for example, a concomitantdrug can be used in 0.01-100 parts by weight relative to 1 part byweight of the compound of the present invention.

EXAMPLES

The present invention is explained in detail in the following byreferring to Examples, Experimental Examples and Formulation Examples,which are not to be construed as limitative, and the invention may bechanged within the scope of the present invention.

In the following Examples, the “room temperature” generally means about10° C. to about 35° C. The ratios indicated for mixed solvents arevolume mixing ratios, unless otherwise specified. % means wt %, unlessotherwise specified.

In silica gel column chromatography, NH means use ofaminopropylsilane-bound silica gel. In HPLC (high performance liquidchromatography), C18 means use of octadecyl-bound silica gel. The ratiosof elution solvents are volume mixing ratios, unless otherwisespecified.

The abbreviations used in the specification mean the following.

THF: tetrahydrofuranDME: 1,2-dimethoxyethane

DMF: N, N-dimethylformamide DMA: N, N-dimethylacetamide

DMSO: dimethyl sulfoxideESI: electrospray methodAPCI: atmospheric chemical ionization[M+H]⁺: molecular ion peakM: mol concentrationIPE: diisopropyl etherWSC: 1-[3-(dimethylamino) propyl]-3-ethylcarbodiimideHATU: 2-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluroniumhexafluorophosphateHOBt: 1-hydroxybenzotriazoleHPLC: high-performance liquid chromatography

DIPEA: N,N-diisopropylethylamine

NMP: N-methyl-2-pyrrolidoneDPPF: 1,1′-bis(diphenylphosphino)ferrocenePd₂(dba)₃: tris(dibenzylideneacetone)dipalladium(0)Xantphos: 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene

¹H NMR (protone nuclear magnetic resonance spectrum) was measured byFourier-transform type NMR. For the analysis, ACD/SpecManager (tradename) and the like were used. Peaks with very mild protons such as ahydroxy group, an amino group and the like are not described.

MS (mass spectrum) was measured by LC/MS (liquid chromatography massspectrometer). As API (Atomospheric Pressure Ionization), ESI (ElectroSpray Ionization) method, or APCI (Atomospheric Pressure ChemicalIonization) method was used. The data indicates those found. Generally,a molecular ion peak is observed. In the case of a compound having atert-butoxycarbonyl group (-Boc), a peak after elimination of atert-butoxycarbonyl group or tert-butyl group may be observed as afragment ion. In the case of a compound having a hydroxy group (—OH), apeak after elimination of H₂O may be observed as a fragment ion. In thecase of a salt, a molecular ion peak or fragment ion peak of free formis generally observed.

The elemental analysis value (Anal.) shows Calculated value (Calcd) andFound value (Found).

Example 11-(4-(4-chloro-1H-pyrazol-1-yl)pyridin-3-yl)-N,N-dimethylpiperidine-4-carboxamideA) 4-(4-chloro-1H-pyrazol-1-yl)-3-fluoropyridine

A mixture of p-toluenesulfonic acid monohydrate (0.58 g),4-chloro-3-fluoropyridine (2.0 g), 4-chloro-1H-pyrazole (1.7 g) and2-propanol (10 mL) was irradiated with microwave at 130° C. for 2 hr.The mixture was allowed to be cooled to room temperature, saturatedaqueous sodium bicarbonate solution was added thereto, and the mixturewas extracted with ethyl acetate. The organic layer was washed withsaturated brine, and dried over anhydrous sodium sulfate, and thesolvent was evaporated under reduced pressure. The residue was purifiedby silica gel column chromatography (ethyl acetate/hexane) to give thetitle compound (2.2 g).

MS (API+). found: 198.2, 200.0.

B) benzyl 4-(dimethylcarbamoyl)piperidine-1-carboxylate

To a mixture of 1-((benzyloxy)carbonyl)piperidine-4-carboxylic acid (1.2g) and DMF (12 mL) were added HATU (2.1 g), triethylamine (0.83 mL) anddimethylamine THF solution (2M, 2.73 mL) at room temperature. Themixture was stirred at room temperature for 4 hr, saturated aqueousammonium chloride solution was added thereto, and the mixture wasextracted with ethyl acetate. The organic layer was washed with waterand saturated brine, and dried over anhydrous sodium sulfate, and thesolvent was evaporated under reduced pressure. The residue was purifiedby silica gel column chromatography (NH, ethyl acetate/hexane) to givethe title compound (960 mg).

MS (API+): [M+H]⁺ 291.2.

C) N,N-dimethylpiperidine-4-carboxamide

Benzyl 4-(dimethylcarbamoyl)piperidine-1-carboxylate (960 mg) wasdissolved in ethanol (15 mL) and ethyl acetate (15 mL), 10% palladiumcarbon (96 mg) was added thereto, and the mixture was stirred at roomtemperature for 5 hr under hydrogen atmosphere. The insoluble substancewas removed by filtration, and the filtrate was concentrated underreduced pressure to give the title compound (530 mg).

¹H NMR (300 MHz, DMSO-d₆) δ 1.31-1.57 (4H, m), 2.45 (1H, d, J=3.0 Hz),2.63 (1H, tt, J=11.1, 4.0 Hz), 2.79 (3H, s), 2.91 (2H, dt, J=12.1, 3.0Hz), 2.99 (3H, s), 3.29 (2H, brs).

D)1-(4-(4-chloro-1H-pyrazol-1-yl)pyridin-3-yl)-N,N-dimethylpiperidine-4-carboxamide

A mixture of 4-(4-chloro-1H-pyrazol-1-yl)-3-fluoropyridine (98 mg),N,N-dimethylpiperidine-4-carboxamide (160 mg), potassium carbonate (140mg) and DMA (0.50 mL) was irradiated with microwave at 200° C. for 10hr. Water was added thereto, and the mixture was extracted with ethylacetate. The organic layer was washed with saturated brine, and driedover anhydrous sodium sulfate, and the solvent was evaporated underreduced pressure. The residue was purified by silica gel columnchromatography (NH, ethyl acetate/hexane), and the obtained solid wascrystallized from ethyl acetate/hexane to give the title compound (39mg).

¹H NMR (300 MHz, DMSO-d₆) δ 1.57-1.74 (4H, m), 2.67-2.79 (3H, m), 2.82(3H, s), 2.86-2.96 (2H, m), 3.02 (3H, s), 7.52 (1H, d, J=5.3 Hz), 7.96(1H, s), 8.36 (1H, d, J=5.3 Hz), 8.48 (1H, s), 8.77 (1H, s).

Example 13(3-exo)-N,N-dimethyl-8-(4-(4-methyl-1H-pyrazol-1-yl)pyridin-3-yl)-8-azabicyclo[3.2.1]octane-3-carboxamideA) tert-butyl3-(dimethylcarbamoyl)-8-azabicyclo[3.2.1]octane-8-carboxylate

A mixture of8-(tert-butoxycarbonyl)-8-azabicyclo[3.2.1]octane-3-carboxylic acid (400mg), dimethylamine hydrochloride (260 mg), HATU (770 mg), DIPEA (0.96mL) and DMF (5.0 mL) was stirred at room temperature for 16 hr. Themixture was diluted with ethyl acetate/water, and extracted with ethylacetate. The organic layer was separated, washed with water andsaturated brine, and dried over sodium sulfate, and the solvent wasevaporated under reduced pressure. The residue was purified by silicagel column chromatography (ethyl acetate/hexane and methanol/ethylacetate) to give the title compound (440 mg).

¹H NMR (300 MHz, CDCl₃) δ 1.45-1.56 (11H, m), 1.60-1.70 (2H, m),1.95-2.07 (4H, m), 2.93 (3H, s), 3.00-3.13 (4H, m), 4.20-4.35 (2H, m).

B) N,N-dimethyl-8-azabicyclo[3.2.1]octane-3-carboxamide hydrochloride

To a mixture of tert-butyl3-(dimethylcarbamoyl)-8-azabicyclo[3.2.1]octane-8-carboxylate (440 mg)and ethyl acetate (4.0 mL) was added 4M hydrogen chloride/ethyl acetate(10 mL), and the mixture was stirred at room temperature for 16 hr, andconcentrated under reduced pressure to give the title compound (340 mg).

¹H NMR (300 MHz, DMSO-d₆) δ 1.59-1.71 (2H, m), 1.86-2.06 (6H, m), 2.81(3H, s), 2.99-3.15 (4H, m), 3.86-4.00 (2H, m), 8.68 (1H, brs), 9.39 (1H,brs).

C) 3-fluoro-4-(4-methyl-1H-pyrazol-1-yl)pyridine

A mixture of p-toluenesulfonic acid monohydrate (0.83 g),4-chloro-3-fluoropyridine (2.9 g), 4-methyl-1H-pyrazole (1.9 mL) and2-propanol (14 mL) was irradiated with microwave at 130° C. for 2 hr. Tothe mixture was added saturated aqueous sodium bicarbonate solution, andthe mixture was extracted with ethyl acetate. The organic layer waswashed with water and saturated brine, and dried over anhydrous sodiumsulfate, and the solvent was evaporated under reduced pressure. Theresidue was purified by silica gel column chromatography (ethylacetate/hexane) to give the title compound (3.3 g).

¹H NMR (300 MHz, DMSO-d₆) δ 2.12 (3H, s), 7.76 (1H, s), 7.93 (1H, dd,J=7.0, 5.5 Hz), 8.18 (1H, dd, J=1.9, 0.8 Hz), 8.49 (1H, d, J=5.3 Hz),8.74 (1H, d, J=4.2 Hz).

D)(3-exo)-N,N-dimethyl-8-(4-(4-methyl-1H-pyrazol-1-yl)pyridin-3-yl)-8-azabicyclo[3.2.1]octane-3-carboxamide

A mixture of N,N-dimethyl-8-azabicyclo[3.2.1]octane-3-carboxamidehydrochloride (170 mg), 3-fluoro-4-(4-methyl-1H-pyrazol-1-yl)pyridine(260 mg), potassium carbonate (320 mg) and NMP (2.0 mL) was stirred withmicrowave irradiation at 200° C. for 16 hr. The mixture was diluted withethyl acetate/water, and extracted with ethyl acetate. The organic layerwas separated, washed with water and saturated brine, and dried oversodium sulfate, and the solvent was evaporated under reduced pressure.The residue was purified by silica gel column chromatography (NH, ethylacetate/hexane), and the obtained solid was recrystallized from ethylacetate/hexane to give the title compound (25 mg).

¹H NMR (300 MHz, CDCl₃) δ 1.45-1.55 (2H, m), 1.63-1.72 (2H, m),1.98-2.13 (4H, m), 2.18 (3H, s), 2.90-3.03 (4H, m), 3.05 (3H, s),3.59-3.67 (2H, m), 7.36 (1H, d, J=5.3 Hz), 7.52 (1H, s), 8.03-8.07 (1H,m), 8.20 (1H, d, J=4.9 Hz), 8.32 (1H, s).

Example 211-(4-(1,3-benzothiazol-2-yl)pyridin-3-yl)-N,N-dimethylpiperidine-4-carboxamideA) 2-(3-fluoropyridin-4-yl)benzo[d]thiazole

To a mixture of 3-fluoroisonicotine acid (1.0 g) and DIPEA (1.9 mL) wereadded 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphorinane-2,4,6-trioxide(1.9 mL, 50% ethyl acetate solution) and 2-aminobenzenethiol (0.76 mL)at room temperature, and the mixture was stirred overnight at 70° C. Themixture was diluted with water and ethyl acetate, and heated to 60° C.The insoluble substance was removed by filtration, and the filtrate wasextracted with ethyl acetate. The organic layer was washed withsaturated brine, and dried over anhydrous magnesium sulfate, and thesolvent was evaporated under reduced pressure. The residue was purifiedby silica gel column chromatography (ethyl acetate/hexane) to give thetitle compound (460 mg).

MS (API+): [M+H]⁺ 231.1.

B)1-(4-(1,3-benzothiazol-2-yl)pyridin-3-yl)-N,N-dimethylpiperidine-4-carboxamide

A mixture of 2-(3-fluoropyridin-4-yl)benzo[d]thiazole (100 mg),N,N-dimethylpiperidine-4-carboxamide (81 mg), potassium carbonate (90mg) and NMP (0.50 mL) was stirred overnight at 150° C. The mixture wasallowed to be cooled to room temperature, diluted with water, andextracted with ethyl acetate. The organic layer was washed withsaturated brine, and dried over anhydrous magnesium sulfate, and thesolvent was evaporated under reduced pressure. The residue was purifiedby silica gel column chromatography (NH, ethyl acetate/hexane), and theobtained solid was recrystallized from ethyl acetate/hexane to give thetitle compound (79 mg).

¹H NMR (400 MHz, CDCl₃) δ 1.86 (2H, d, J=13.0 Hz), 2.24-2.37 (2H, m),2.72 (1H, tt, J=11.6, 3.6 Hz), 2.93-3.04 (5H, m), 3.12 (3H, s), 3.29(2H, d, J=11.7 Hz), 7.41-7.48 (1H, m), 7.52 (1H, td, J=7.6, 1.2 Hz),8.00 (1H, d, J=7.8 Hz), 8.11 (1H, d, J=8.1 Hz), 8.25 (1H, d, J=5.1 Hz),8.52 (1H, d, J=5.1 Hz), 8.66 (1H, s).

Example 33(2R)-1-((1-(4-(4-chloro-1H-pyrazol-1-yl)pyridin-3-yl)piperidin-4-yl)carbonyl)pyrrolidine-2-carbonitrileA) ethyl1-(4-(4-chloro-1H-pyrazol-1-yl)pyridin-3-yl)piperidine-4-carboxylate

A mixture of 4-(4-chloro-1H-pyrazol-1-yl)-3-fluoropyridine (3.4 g),ethyl piperidine-4-carboxylate (13 mL), potassium carbonate (7.1 g) andNMP (15 mL) was stirred at 180° C. for 4 hr. To the mixture was addedwater at 0° C., and the mixture was extracted with ethyl acetate. Theorganic layer was washed with water and saturated brine, and dried overanhydrous sodium sulfate, and the solvent was evaporated under reducedpressure. The residue was purified by silica gel column chromatography(ethyl acetate/hexane) to give the title compound (5.3 g).

¹H NMR (300 MHz, DMSO-d₆) δ 1.16-1.23 (3H, m), 1.56-1.74 (2H, m),1.80-1.93 (2H, m), 2.37-2.46 (1H, m), 2.66-2.79 (2H, m), 2.89 (2H, dt,J=12.1, 3.2 Hz), 4.09 (2H, q, J=7.2 Hz), 7.52 (1H, d, J=4.9 Hz), 7.96(1H, s), 8.36 (1H, d, J=4.9 Hz), 8.48 (1H, s), 8.77 (1H, s).

B) 1-(4-(4-chloro-1H-pyrazol-1-yl)pyridin-3-yl)piperidine-4-carboxylicacid

Ethyl1-(4-(4-chloro-1H-pyrazol-1-yl)pyridin-3-yl)piperidine-4-carboxylate(5.3 g) was dissolved in THF (55 mL) and ethanol (20 mL), to the mixturewas added 2M aqueous sodium hydroxide solution (12 mL), and the mixturewas stirred overnight at room temperature. The mixture was neutralizedwith 1M hydrochloric acid (24 mL), and the precipitated solid wascollected by filtration to give the title compound (4.0 g).

¹H NMR (300 MHz, DMSO-d₆) δ 1.55-1.71 (2H, m), 1.84 (2H, dd, J=13.3, 3.0Hz), 2.25-2.39 (1H, m), 2.64-2.76 (2H, m), 2.89 (2H, dt, J=12.0, 3.3Hz), 7.52 (1H, d, J=5.3 Hz), 7.96 (1H, s), 8.36 (1H, d, J=5.3 Hz), 8.48(1H, s), 8.77 (1H, s), 12.27 (1H, brs).

C)(2R)-1-((1-(4-(4-chloro-1H-pyrazol-1-yl)pyridin-3-yl)piperidin-4-yl)carbonyl)pyrrolidine-2-carbonitrile

To a mixture of1-(4-(4-chloro-1H-pyrazol-1-yl)pyridin-3-yl)piperidine-4-carboxylic acid(300 mg) and DMF (6.0 mL) were added HATU (480 mg), triethylamine (0.30mL) and (R)-pyrrolidine-2-carbonitrile hydrochloride (160 mg) at roomtemperature, and the mixture was stirred for 2 hr. To the mixture wasadded water, and the mixture was extracted with ethyl acetate. Theorganic layer was washed with water and saturated brine, and dried overanhydrous sodium sulfate, and the solvent was evaporated under reducedpressure. The residue was purified by silica gel column chromatography(NH, ethyl acetate/hexane), and the obtained solid was crystallized fromethyl acetate/hexane to give the title compound (290 mg).

¹H NMR (300 MHz, DMSO-d₆) δ 1.60-1.84 (4H, m), 1.95-2.31 (4H, m),2.66-3.04 (5H, m), 3.36-3.59 (1H, m), 3.60-3.75 (1H, m), 4.72 (1H, dd,J=7.6, 3.8 Hz), 7.52 (1H, d, J=4.9 Hz), 7.97 (1H, s), 8.36 (1H, d, J=4.9Hz), 8.49 (1H, s), 8.78 (1H, s).

Example 431-(4-(4-bromo-1H-pyrazol-1-yl)pyridin-3-yl)-N,N-dimethylpiperidine-4-carboxamideA) 4-(4-bromo-1H-pyrazol-1-yl)-3-fluoropyridine

A mixture of p-toluenesulfonic acid monohydrate (0.30 g),4-chloro-3-fluoropyridine (1.0 g), 4-bromo-1H-pyrazole (1.3 g) and2-propanol (5.0 mL) was irradiated with microwave at 130° C. for 2 hr.The mixture was allowed to be cooled to room temperature, saturatedaqueous sodium bicarbonate solution was added thereto, and the mixturewas extracted with ethyl acetate. The organic layer was washed withsaturated brine, and dried over anhydrous sodium sulfate, and thesolvent was evaporated under reduced pressure. The residue was purifiedby silica gel column chromatography (ethyl acetate/hexane) to give thetitle compound (1.5 g).

MS (API+). found: 242.0, 244.0.

B)1-(4-(4-bromo-1H-pyrazol-1-yl)pyridin-3-yl)-N,N-dimethylpiperidine-4-carboxamide

A mixture of 4-(4-bromo-1H-pyrazol-1-yl)-3-fluoropyridine (700 mg),N,N-dimethylpiperidine-4-carboxamide (680 mg), potassium carbonate (800mg) and NMP (2.5 mL) was heated at 180° C. for 5 hr. The mixture wasallowed to be cooled to room temperature, water was added thereto, andthe mixture was extracted with ethyl acetate. The organic layer waswashed with water and saturated brine, and dried over anhydrous sodiumsulfate, and the solvent was evaporated under reduced pressure. Theresidue was purified by silica gel column chromatography (NH, ethylacetate/hexane), and the obtained solid was crystallized from ethylacetate/hexane/IPE to give the title compound (410 mg).

¹H NMR (300 MHz, DMSO-d₆) δ 1.49-1.78 (4H, m), 2.64-2.84 (6H, m),2.86-2.96 (2H, m), 3.02 (3H, s), 7.52 (1H, d, J=4.9 Hz), 7.96 (1H, s),8.36 (1H, d, J=5.3 Hz), 8.48 (1H, s), 8.77 (1H, d, J=0.8 Hz).

Example 541-(4-(4-chloro-1H-pyrazol-1-yl)pyridin-3-yl)-N-methyl-N-(tetrahydro-2H-pyran-4-yl)piperidine-4-carboxamide

A mixture of1-(4-(4-chloro-1H-pyrazol-1-yl)pyridin-3-yl)piperidine-4-carboxylic acid(0.50 g), N-methyltetrahydro-2H-pyran-4-amine (0.16 g), HATU (0.81 g),triethylamine (0.91 mL) and DMF (8.2 mL) was stirred at room temperaturefor 3 hr. To the mixture was added water, and the mixture was extractedwith ethyl acetate. The organic layer was washed with water andsaturated brine, and dried over anhydrous magnesium sulfate, and thesolvent was evaporated under reduced pressure. The residue was purifiedby silica gel column chromatography (NH, ethyl acetate/hexane), and theobtained solid was crystallized from ethyl acetate/hexane to give thetitle compound (0.43 g).

¹H NMR (300 MHz, CDCl₃) δ1.45-1.65 (2H, m), 1.65-2.11 (6H, m), 2.61 (1H,brs), 2.71-2.97 (5H, m), 3.13 (2H, d, J=11.7 Hz), 3.37-3.59 (2H, m),3.94-4.16 (2H, m), 4.66-4.84 (1H, m), 7.59 (1H, s), 7.66 (1H, s), 8.40(1H, s), 8.46 (1H, s), 8.59 (1H, s).

Example 581-(4-(4-chloro-1H-pyrazol-1-yl)pyridin-3-yl)-N-cyclopropyl-N-methylpiperidine-4-carboxamide

To a mixture of1-(4-(4-chloro-1H-pyrazol-1-yl)pyridin-3-yl)piperidine-4-carboxylic acid(0.5 g) and DMF (8.2 mL) were added HATU (0.81 g), triethylamine (0.91mL) and N-methylcyclopropanamine (0.14 g), and the mixture was stirredat room temperature for 3 hr. To the mixture was added water, and themixture was extracted with ethyl acetate. The organic layer was washedwith water and saturated brine, and dried over anhydrous magnesiumsulfate, and the solvent was evaporated under reduced pressure. Theresidue was purified by silica gel column chromatography (NH, ethylacetate/hexane), and the obtained solid was crystallized from ethylacetate/hexane to give the title compound (0.40 g).

¹H NMR (300 MHz, CDCl₃) δ 0.71-0.99 (4H, m), 1.71-1.85 (2H, m), 1.96(2H, dd, J=12.3, 2.8 Hz), 2.64-2.85 (3H, m), 2.94 (3H, s), 3.06-3.22(3H, m), 7.60 (1H, d, J=4.9 Hz), 7.66 (1H, s), 8.37 (1H, s), 8.46 (1H,s), 8.62 (1H, s).

Example 591-(4-(4-cyclopropyl-1H-pyrazol-1-yl)pyridin-3-yl)-N,N-dimethylpiperidine-4-carboxamide

A mixture of1-(4-(4-bromo-1H-pyrazol-1-yl)pyridin-3-yl)-N,N-dimethylpiperidine-4-carboxamide(80 mg), cyclopropylboronic acid (36 mg),1,1′-bis(diphenylphosphino)ferrocene-palladium(II) dichloridedichloromethane complex (17 mg), cesium carbonate (210 mg), DME (1.5 mg)and water (0.30 mg) was irradiated with microwave at 100° C. for 30 min.1,1′-Bis(diphenylphosphino)ferrocene-palladium(II) dichloridedichloromethane complex (17 mg) and cyclopropylboronic acid (36 mg) wereadded thereto, and the mixture was irradiated with microwave at 100° C.for 1 hr. Saturated aqueous sodium bicarbonate solution was addedthereto, and the mixture was extracted with ethyl acetate. The organiclayer was washed with saturated brine, and dried over anhydrous sodiumsulfate, and the solvent was evaporated under reduced pressure. Theresidue was purified by silica gel column chromatography (NH, ethylacetate/hexane), and then purified by HPLC (C18, mobile phase:water/acetonitrile (containing 0.1% TFA)). To the obtained fractions wasadded saturated aqueous sodium hydrogen carbonate solution, and themixture was extracted with ethyl acetate. The organic layer was driedover anhydrous sodium sulfate, and concentrated under reduced pressure,and the obtained solid was crystallized from ethyl acetate/hexane togive the title compound (15 mg).

¹H NMR (300 MHz, CDCl₃) δ 0.56-0.63 (2H, m), 0.88-0.96 (2H, m),1.73-1.83 (3H, m), 1.86-2.02 (2H, m), 2.56-2.67 (1H, m), 2.73 (2H, td,J=11.9, 2.3 Hz), 2.98 (3H, s), 3.08 (3H, s), 3.09-3.17 (2H, m), 7.49(1H, s), 7.60 (1H, d, J=5.3 Hz), 8.34 (1H, d, J=5.3 Hz), 8.36 (1H, s),8.40 (1H, s).

Example 681-(4-(4-methyl-1H-pyrazol-1-yl)pyridin-3-yl)-N-(tetrahydro-2H-pyran-4-yl)piperidine-4-carboxamide

A mixture of1-(4-(4-methyl-1H-pyrazol-1-yl)pyridin-3-yl)piperidine-4-carboxylic acid(1.0 g), tetrahydro-2H-pyran-4-amine (0.36 mL), HATU (1.7 g),triethylamine (1.9 mL) and DMF (12 mL) was stirred at room temperaturefor 3 hr. To the mixture was added water, and the mixture was extractedwith ethyl acetate. The organic layer was washed with water andsaturated brine, and dried over anhydrous magnesium sulfate, and thesolvent was evaporated under reduced pressure. The residue was purifiedby silica gel column chromatography (NH, ethyl acetate/hexane), and theobtained solid was crystallized from ethyl acetate/hexane to give thetitle compound (0.78 g).

¹H NMR (300 MHz, CDCl₃) δ 1.35-1.54 (2H, m), 1.78-1.98 (6H, m),2.06-2.21 (4H, m), 2.70 (2H, dt, J=11.7, 7.2 Hz), 3.12 (2H, d, J=12.1Hz), 3.48 (2H, td, J=11.7, 2.3 Hz), 3.88-4.09 (3H, m), 5.37 (1H, d,J=7.6 Hz), 7.54 (1H, s), 7.60 (1H, d, J=5.3 Hz), 8.30-8.36 (2H, m), 8.39(1H, s).

Example 70(2R)-1-((1-(4-(4-methyl-1H-pyrazol-1-yl)pyridin-3-yl)piperidin-4-yl)carbonyl)pyrrolidine-2-carbonitrileA) ethyl1-(4-(4-methyl-1H-pyrazol-1-yl)pyridin-3-yl)piperidine-4-carboxylate

A mixture of 3-fluoro-4-(4-methyl-1H-pyrazol-1-yl)pyridine (2.5 g),ethyl piperidine-4-carboxylate (4.3 mL), potassium carbonate (5.8 g) andNMP (12 mL) was stirred at 180° C. for 7 hr. To the mixture was addedethyl piperidine-4-carboxylate (2.0 mL) at room temperature, and themixture was stirred at 180° C. for 2 hr, and then overnight at roomtemperature. To the mixture was added water at 0° C., and the mixturewas extracted with ethyl acetate. The organic layer was washed withwater and saturated brine, and dried over anhydrous sodium sulfate, andthe solvent was evaporated under reduced pressure. The residue waspurified by silica gel column chromatography (ethyl acetate/hexane) togive the title compound (2.8 g).

MS (API+): [M+H]⁺ 315.2.

B) 1-(4-(4-methyl-1H-pyrazol-1-yl)pyridin-3-yl)piperidine-4-carboxylicacid

To a solution of ethyl1-(4-(4-methyl-1H-pyrazol-1-yl)pyridin-3-yl)piperidine-4-carboxylate(1.2 g), THF (15 mL) and ethanol (5.0 mL) was added 2M aqueous sodiumhydroxide solution (3.0 mL), and the mixture was stirred overnight atroom temperature. The mixture was cooled to 0° C., and neutralized with1M hydrochloric acid (6.0 mL). The precipitated solid was collected byfiltration, and washed with water to give the title compound (0.84 g).

MS (API+): [M+H]⁺ 287.2.

C)(2R)-1-((1-(4-(4-methyl-1H-pyrazol-1-yl)pyridin-3-yl)piperidin-4-yl)carbonyl)pyrrolidine-2-carbonitrile

To a solution of1-(4-(4-methyl-1H-pyrazol-1-yl)pyridin-3-yl)piperidine-4-carboxylic acid(0.25 g) and DMF (6.0 mL) were added HATU (0.43 g), triethylamine (0.27mL) and (R)-pyrrolidine-2-carbonitrile hydrochloride (0.14 g) at roomtemperature, and the mixture was stirred for 2 hr. To the mixture wasadded water, and the mixture was extracted with ethyl acetate. Theorganic layer was washed with water and saturated brine, and dried overanhydrous sodium sulfate, and the solvent was evaporated under reducedpressure. The residue was purified by silica gel column chromatography(NH, ethyl acetate/hexane), and the obtained solid was crystallized fromethyl acetate/hexane to give the title compound (0.22 g).

¹H NMR (300 MHz, DMSO-d₆) δ 1.64-1.83 (4H, m), 1.97-2.07 (2H, m),2.10-2.21 (5H, m), 2.54-2.61 (1H, m), 2.69-2.81 (2H, m), 2.89-3.04 (2H,m), 3.49-3.59 (1H, m), 3.63-3.73 (1H, m), 4.72 (1H, dd, J=7.6, 3.8 Hz),7.54 (1H, d, J=5.3 Hz), 7.63 (1H, s), 8.31 (1H, d, J=5.3 Hz), 8.42 (1H,s), 8.44 (1H, s).

Example 70 (Another Production Method)(2R)-1-((1-(4-(4-methyl-1H-pyrazol-1-yl)pyridin-3-yl)piperidin-4-yl)carbonyl)pyrrolidine-2-carbonitrileA) ethyl1-(4-(4-methyl-1H-pyrazol-1-yl)pyridin-3-yl)piperidine-4-carboxylate

A mixture of 3-fluoro-4-(4-methyl-1H-pyrazol-1-yl)pyridine (0.80 g),ethyl piperidine-4-carboxylate (1.5 mL) and NMP (4.5 mL) was stirred at185° C. for 8.5 hr. The mixture was purified by silica gel columnchromatography (ethyl acetate/hexane) to give the title compound (1.0g).

¹H NMR (300 MHz, DMSO-d₆) δ 1.19 (3H, t, J=7.2 Hz), 1.60-1.76 (2H, m),1.81-1.93 (2H, m), 2.12 (3H, s), 2.37-2.48 (1H, m), 2.65-2.77 (2H, m),2.88-2.99 (2H, m), 4.09 (2H, q, J=7.2 Hz), 7.53 (1H, d, J=4.9 Hz), 7.63(1H, s), 8.31 (1H, d, J=5.3 Hz), 8.41 (1H, s), 8.42 (1H, s).

B) 1-(4-(4-methyl-1H-pyrazol-1-yl)pyridin-3-yl)piperidine-4-carboxylicacid

To a solution of ethyl1-(4-(4-methyl-1H-pyrazol-1-yl)pyridin-3-yl)piperidine-4-carboxylate(2.8 g), THF (30 mL) and ethanol (10 mL) was added 2M aqueous sodiumhydroxide solution (7.0 mL), and the mixture was stirred overnight atroom temperature. The mixture was neutralized with 1M hydrochloric acid(14 mL) at 0° C. The obtained solid was collected by filtration, andwashed with water to give the title compound (2.2 g).

¹H NMR (300 MHz, DMSO-d₆) δ 1.54-1.75 (2H, m), 1.78-1.92 (2H, m), 2.12(3H, s), 2.25-2.41 (1H, m), 2.63-2.75 (2H, m), 2.86-2.98 (2H, m), 7.53(1H, d, J=4.9 Hz), 7.63 (1H, s), 8.30 (1H, d, J=5.3 Hz), 8.39-8.45 (2H,m), 12.33 (1H, brs).

C)(2R)-1-((1-(4-(4-methyl-1H-pyrazol-1-yl)pyridin-3-yl)piperidin-4-yl)carbonyl)pyrrolidine-2-carbonitrile(crude crystals)

To a suspension of1-(4-(4-methyl-1H-pyrazol-1-yl)pyridin-3-yl)piperidine-4-carboxylic acid(80 g) and acetonitrile (0.32 L) were added DIPEA (0.21 L),(R)-prolinamide (40 g) and2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphorinane-2,4,6-trioxide (1.7Methyl acetate solution, 0.28 L) at 0° C. The mixture was stirred at roomtemperature for 1 hr, to the mixture was added2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphorinane-2,4,6-trioxide (1.7Methyl acetate solution, 0.35 L), and the mixture was stirred overnightat 70° C. To the mixture was added saturated aqueous sodium hydrogencarbonate solution (1600 mL) at 0° C., and the mixture was extractedwith a mixed solvent of ethyl acetate and THF. The organic layer waswashed with saturated brine, and dried over anhydrous magnesium sulfate,and the solution was purified by silica gel column chromatography (ethylacetate). The solvent was evaporated under reduced pressure, to theresidue was added diisopropyl ether, and the mixture was stirredovernight at room temperature. The solid was collected by filtration,and washed with diisopropyl ether to give the title compound (93 g).

¹H NMR (300 MHz, DMSO-d₆) δ 1.57-1.82 (4H, m), 1.89-2.30 (7H, m),2.53-2.83 (3H, m), 2.86-3.06 (2H, m), 3.41-3.58 (1H, m), 3.62-3.75 (1H,m), 4.72 (1H, dd, J=7.4, 4.0 Hz), 7.53 (1H, d, J=5.3 Hz), 7.63 (1H, s),8.31 (1H, d, J=5.3 Hz), 8.41 (1H, s), 8.43 (1H, s).

D)(2R)-1-((1-(4-(4-methyl-1H-pyrazol-1-yl)pyridin-3-yl)piperidin-4-yl)carbonyl)pyrrolidine-2-carbonitrile

The crystals (103 g) of(2R)-1-((1-(4-(4-methyl-1H-pyrazol-1-yl)pyridin-3-yl)piperidin-4-yl)carbonyl)pyrrolidine-2-carbonitrilewere dissolved in ethanol (620 mL) at 70° C., heptane (620 mL) was addeddropwise thereto at the same temperature, and the mixture was stirredfor 1 hr. Heptane (820 mL) was added again thereto over 1 hr, and themixture was stirred overnight at room temperature. The crystals werecollected by filtration, and washed with heptane (1.0 L) to give thetitle compound (92 g).

¹H NMR (300 MHz, DMSO-d₆) δ 1.59-1.83 (4H, m), 1.89-2.29 (7H, m),2.53-2.82 (3H, m), 2.88-3.07 (2H, m), 3.43-3.58 (1H, m), 3.66-3.72 (1H,m), 4.72 (1H, dd, J=7.6, 3.8 Hz), 7.53 (1H, d, J=4.9 Hz), 7.63 (1H, s),8.31 (1H, d, J=5.3 Hz), 8.41 (1H, s), 8.43 (1H, s).

mp: 178° C.

Example 791-(4-(4-chloro-1H-pyrazol-1-yl)pyridin-3-yl)-3,3-difluoro-N-(tetrahydro-2H-pyran-4-yl)piperidine-4-carboxamideA) 3-(4-((benzyloxy)methyl)-3,3-difluoropiperidin-1-yl)-4-chloropyridine

A mixture of 4-((benzyloxy)methyl)-3, 3-difluoropiperidine (560 mg),3-bromo-4-chloropyridine (490 mg), palladium acetate (26 mg), Xantphos(140 mg), sodium tert-butoxide (340 mg) and toluene (12 mL) was stirredwith microwave irradiation at 120° C. for 3 hr. The mixture was filteredthrough NH-silica gel pad (ethyl acetate), and the filtrate wasconcentrated under reduced pressure. The residue was purified by silicagel column chromatography (ethyl acetate/hexane), and then silica gelcolumn chromatography (NH, ethyl acetate/hexane) to give the titlecompound (550 mg).

¹H NMR (300 MHz, CDCl₃) δ 1.74-1.92 (1H, m), 2.13-2.37 (2H, m),2.83-2.94 (1H, m), 2.98-3.15 (1H, m), 3.44-3.56 (2H, m), 3.59-3.71 (1H,m), 3.94 (1H, dd, J=9.3, 4.0 Hz), 4.53 (1H, d, J=12.0 Hz), 4.59 (1H, d,J=12.0 Hz), 7.27-7.40 (6H, m), 8.21 (1H, d, J=4.9 Hz), 8.29 (1H, s).

B)3-(4-((benzyloxy)methyl)-3,3-difluoropiperidin-1-yl)-4-(4-chloro-1H-pyrazol-1-yl)pyridine

A mixture of3-(4-((benzyloxy)methyl)-3,3-difluoropiperidin-1-yl)-4-chloropyridine(1.9 g), 4-chloro-1H-pyrazole (0.72 g), p-toluenesulfonic acidmonohydrate (0.21 g) and 2-propanol (12 mL) was stirred with microwaveirradiation at 150° C. for 6 hr. The mixture was diluted with ethylacetate/saturated aqueous sodium bicarbonate solution, and extractedwith ethyl acetate. The organic layer was separated, washed with waterand saturated brine, and dried over sodium sulfate, and the solvent wasevaporated under reduced pressure. The residue was purified by silicagel column chromatography (NH, ethyl acetate/hexane) to give the titlecompound (1.5 g).

¹H NMR (300 MHz, CDCl₃) δ 1.59-1.74 (1H, m), 2.05-2.33 (2H, m),2.65-2.79 (1H, m), 2.94-3.16 (2H, m), 3.27-3.40 (1H, m), 3.52 (1H, t,J=8.9 Hz), 3.92 (1H, dd, J=9.3, 4.0 Hz), 4.53 (1H, d, J=12.0 Hz), 4.57(1H, d, J=12.0 Hz), 7.27-7.40 (5H, m), 7.63 (1H, d, J=5.3 Hz), 7.67 (1H,s), 8.42 (1H, s), 8.44 (1H, d, J=4.9 Hz), 8.52 (1H, s).

C)(1-(4-(4-chloro-1H-pyrazol-1-yl)pyridin-3-yl)-3,3-difluoropiperidin-4-yl)methanol

To a mixture of3-(4-((benzyloxy)methyl)-3,3-difluoropiperidin-1-yl)-4-(4-chloro-1H-pyrazol-1-yl)pyridine(1.5 g) and acetonitrile (30 mL) was added trimethylsilyl iodide (5.0mL) under ice-cooling, and the mixture was stirred at room temperaturefor 20 hr. To the mixture was added water under ice-cooling, and themixture was stirred at the same temperature for 10 min. To the mixturewere added pyridine (15 mL), aqueous sodium thiosulfate solution andsaturated aqueous sodium bicarbonate solution, and the mixture wasextracted with ethyl acetate. The organic layer was separated, washedwith water and saturated brine, and dried over sodium sulfate, and thesolvent was evaporated under reduced pressure. The residue was purifiedby silica gel column chromatography (NH, ethyl acetate/hexane andmethanol/ethyl acetate) to give the title compound (0.91 g).

¹H NMR (300 MHz, CDCl₃) δ 1.57-1.78 (2H, m), 1.90-2.21 (2H, m),2.70-2.83 (1H, m), 2.95-3.17 (2H, m), 3.29-3.42 (1H, m), 3.70-3.81 (1H,m), 4.03-4.12 (1H, m), 7.64 (1H, d, J=5.3 Hz), 7.68 (1H, s), 8.43 (1H,s), 8.46 (1H, d, J=5.3 Hz), 8.51 (1H, s).

D) (1r,3s,5R,7S)-1-methyl-2-oxo-2-azaadamantan-2-ium tetrafluoroborate

To a mixture of 1-methyl-2-azaadamantane N-oxyl (1.5 g) and water (5.0mL) was added dropwise 42% aqueous tetrafluoroboric acid solution (1.9mL) over 30 min at room temperature. After confirming that the reactionsolution became golden brown, aqueous sodium hypochlorite solution (6.1mL) was added thereto over 1 hr under ice-cooling, and the mixture wasstirred at the same temperature for an additional 1 hr. The precipitatewas collected by filtration, washed with ice-cooled 5% aqueous sodiumbicarbonate (15 mL), water (15 mL) and ice-cooled diethyl ether (75 mL),and dried at 50° C. for 24 hr to give the title compound (850 mg).

Anal. Calcd for C₁₀H₁₆BF₄NO: C, 47.46; H, 6.37; N, 5.49. Found: C,47.47; H, 6.40; N, 5.50.

E)1-(4-(4-chloro-1H-pyrazol-1-yl)pyridin-3-yl)-3,3-difluoropiperidine-4-carboxylicacid

To a mixture of(1-(4-(4-chloro-1H-pyrazol-1-yl)pyridin-3-yl)-3,3-difluoropiperidin-4-yl)methanol(0.91 g) and acetonitrile (20 mL)/pH 6.8 phosphoric acid buffer solution(10 mL) were added successively sodium chlorite (1.3 g) and(1r,3s,5R,7S)-1-methyl-2-oxo-2-azaadamantan-2-ium tetrafluoroborate (42mg). The mixture was stirred at room temperature for 1.5 hr,2-methylbut-2-ene (6.0 mL) was added thereto, and the mixture wasstirred for an additional 15 min. The large part of the solvent wasevaporated, water was added thereto, and the mixture was stirred underice-cooling for 30 min. The resulting precipitate was collected byfiltration, washed with water and diethyl ether, and dried to give thetitle compound (0.85 g).

¹H NMR (400 MHz, DMSO-d₆) δ 1.82-2.00 (2H, m), 2.79-2.94 (2H, m),3.00-3.13 (1H, m), 3.19-3.34 (2H, m), 7.58 (1H, d, J=5.1 Hz), 7.99 (1H,d, J=0.5 Hz), 8.43 (1H, d, J=5.4 Hz), 8.57 (1H, s), 8.63 (1H, d, J=0.5Hz), 12.90 (1H, brs).

F)1-(4-(4-chloro-1H-pyrazol-1-yl)pyridin-3-yl)-3,3-difluoro-N-(tetrahydro-2H-pyran-4-yl)piperidine-4-carboxamide

A mixture of1-(4-(4-chloro-1H-pyrazol-1-yl)pyridin-3-yl)-3,3-difluoropiperidine-4-carboxylicacid (30 mg), tetrahydropyran-4-ylamine (12 mg), HATU (43 mg), DIPEA (20μL) and DMF (1.0 mL) was stirred at room temperature for 1 hr. Themixture was diluted with ethyl acetate/water, and extracted with ethylacetate. The organic layer was separated, washed with water andsaturated brine, and dried over sodium sulfate, and the solvent wasevaporated under reduced pressure. The residue was purified by silicagel column chromatography (NH, ethyl acetate/hexane and methanol/ethylacetate) to give the title compound (30 mg).

¹H NMR (300 MHz, CDCl₃) δ 1.43-1.59 (2H, m), 1.87-2.01 (2H, m),2.05-2.15 (2H, m), 2.64-2.83 (2H, m), 3.02-3.25 (2H, m), 3.41-3.56 (3H,m), 3.90-4.11 (3H, m), 5.80 (1H, d, J=5.7 Hz), 7.63 (1H, d, J=5.3 Hz),7.68 (1H, s), 8.43-8.50 (3H, m).

Example 822-methyl-8-(4-(4-methyl-1H-pyrazol-1-yl)pyridin-3-yl)-2,8-diazaspiro[4.5]decan-1-oneA) 1-tert-butyl 4-ethyl 4-(cyanomethyl)piperidine-1,4-dicarboxylate

To a mixture of diisopropylamine (4.7 g) and THF (75 mL) was addedn-butyllithium hexane solution (1.6 M, 29 mL) under ice-cooling, and themixture was stirred for 30 min. To the mixture was added a mixture of1-tert-butyl 4-ethyl piperidine-1,4-dicarboxylate (6.0 g) and THF (10mL) under ice-cooling, the mixture was stirred under ice-cooling for 3hr, and 2-bromoacetonitrile (5.6 g) was added thereto under ice-cooling.The mixture was stirred for 12 hr, and the solvent was evaporated underreduced pressure. Water was added thereto, and the mixture was extractedwith ethyl acetate. The organic layer was dried over anhydrous magnesiumsulfate, and the solvent was evaporated under reduced pressure. Theresidue was purified by silica gel column chromatography (ethylacetate/hexane) to give the title compound (2.6 g).

¹H NMR (300 MHz, DMSO-d₆) δ 1.21 (3H, t, J=7.0 Hz), 1.39 (9H, s),1.43-1.54 (2H, m), 1.90-2.00 (2H, m), 2.87 (2H, s), 2.96-3.12 (2H, m),3.57-3.67 (2H, m), 4.11-4.22 (2H, m).

B) tert-butyl 1-oxo-2,8-diazaspiro[4.5]decane-8-carboxylate

To a mixture of 1-tert-butyl 4-ethyl4-(cyanomethyl)piperidine-1,4-dicarboxylate (2.5 g), cobalt(IT) chloridehexahydrate (1.0 g) and methanol (50 mL) was added sodium borohydride(1.6 g) under ice-cooling, and the mixture was stirred under ice-coolingfor 2 hr, and then at room temperature for 2 days, and then 60° C. for 1hr. 28% Aqueous ammonia was added thereto, the precipitate was removedby filtration, and the filtrate was extract with ethyl acetate. Theorganic layer was dried over anhydrous magnesium sulfate, and thesolvent was evaporated under reduced pressure. The residue was purifiedby silica gel column chromatography (ethyl acetate) to give the titlecompound (1.1 g).

¹H NMR (300 MHz, DMSO-d₆) δ 1.25-1.35 (2H, m), 1.40 (9H, s), 1.45-1.58(2H, m), 1.90-1.98 (2H, m), 2.90 (2H, brs), 3.16 (2H, t, J=7.2 Hz),3.76-3.86 (2H, m), 7.56 (1H, brs).

C) 2,8-diazaspiro[4.5]decan-1-one hydrochloride

To a mixture of tert-butyl 1-oxo-2,8-diazaspiro[4.5]decane-8-carboxylate(400 mg), ethyl acetate (10 mL) and ethanol (2.0 mL) was added 4 Mhydrogen chloride/ethyl acetate solution (5.0 mL) at room temperature,the mixture was stirred at 60° C. for 2 hr, and the solvent wasevaporated under reduced pressure. The residue was diluted with ethylacetate, and the obtained solid was collected by filtration to give thetitle compound (240 mg).

¹H NMR (300 MHz, CDCl₃) δ 1.47-1.64 (2H, m), 1.77-1.92 (2H, m),1.93-2.03 (2H, m), 2.81-3.03 (2H, m), 3.11-3.34 (4H, m), 7.72 (1H, brs),8.62-9.33 (2H, m).

D)8-(4-(4-methyl-1H-pyrazol-1-yl)pyridin-3-yl)-2,8-diazaspiro[4.5]decan-1-one

A mixture of 3-fluoro-4-(4-methyl-1H-pyrazol-1-yl)pyridine (50 mg),2,8-diazaspiro[4.5]decan-1-one hydrochloride (54 mg), potassiumcarbonate (120 mg) and NMP (0.20 mL) was stirred at 160° C. for 1 day,and then at 180° C. for 7 hr. The mixture was allowed to be cooled toroom temperature, diluted with water, and extracted with ethyl acetate.The organic layer was washed with saturated brine, and dried overanhydrous magnesium sulfate, and the solvent was evaporated underreduced pressure. The residue was purified by silica gel columnchromatography (NH, methanol/ethyl acetate) to give the title compound(36 mg).

MS (API+): [M+H]⁺ 312.2.

E)2-methyl-8-(4-(4-methyl-1H-pyrazol-1-yl)pyridin-3-yl)-2,8-diazaspiro[4.5]decan-1-one

To a mixture of8-(4-(4-methyl-1H-pyrazol-1-yl)pyridin-3-yl)-2,8-diazaspiro[4.5]decan-1-one(35 mg) and DMF (0.50 mL) was added sodium hydride (60%, 6.7 mg) underice-cooling. The mixture was stirred at room temperature for 30 minunder nitrogen atmosphere, to the mixture was added a mixture of methyliodide (7.0 μL) and DMF (0.50 mL), and the mixture was stirred at roomtemperature for 1 hr. To the mixture was added water, and the mixturewas extracted with ethyl acetate. The organic layer was separated,washed with saturated brine, and dried over anhydrous magnesium sulfate,and the solvent was evaporated under reduced pressure. The residue waspurified by silica gel column chromatography (NH, ethyl acetate/hexane),and the obtained solid was recrystallized from ethyl acetate/hexane togive the title compound (18 mg).

¹H NMR (300 MHz, CDCl₃) δ 1.46 (2H, d, J=13.6 Hz), 1.95-2.12 (4H, m),2.17 (3H, s), 2.76 (2H, td, J=12.0, 2.5 Hz), 2.87 (3H, s), 3.08 (2H, dt,J=12.1, 3.4 Hz), 3.27-3.37 (2H, m), 7.53 (1H, s), 7.60 (1H, d, J=5.3Hz), 8.34 (1H, d, J=5.3 Hz), 8.40 (2H, d, J=4.9 Hz).

Example 831-(4-(4-cyano-1H-pyrazol-1-yl)pyridin-3-yl)-N,N-dimethylpiperidine-4-carboxamide

A mixture of1-(4-(4-bromo-1H-pyrazol-1-yl)pyridin-3-yl)-N,N-dimethylpiperidine-4-carboxamide(60 mg), Pd₂(dba)₃ (15 mg), zinc cyanide (56 mg), DPPF (18 mg) andanhydrous DMF (1.5 mL) was heated at 100° C. for 7 hr under argonatmosphere. The mixture was allowed to be cooled to room temperature, tothe mixture was added again Pd₂(dba)₃ (7.0 mg), and the mixture washeated at 100° C. for 5 hr under argon atmosphere. The mixture wasallowed to be cooled to room temperature, and the insoluble substancewas removed by filtration. To the filtrate were added ethyl acetate andwater, and the organic layer was washed with water and saturated brine,dried over anhydrous sodium sulfate, and concentrated under reducedpressure. The residue was purified by silica gel column chromatography(NH, ethyl acetate/hexane), and then purified by HPLC (C18, mobilephase: water/acetonitrile (containing 0.1% TFA)). To the obtainedfractions was added saturated aqueous sodium hydrogen carbonatesolution, and the mixture was extracted with ethyl acetate. The organiclayer was dried over anhydrous sodium sulfate, and concentrated underreduced pressure, and the obtained solid was crystallized from ethylacetate/THF/hexane to give the title compound (17 mg).

¹H NMR (300 MHz, DMSO-d₆) δ 1.58-1.69 (4H, m), 2.65-2.91 (8H, m), 3.01(3H, s), 7.54 (1H, d, J=5.3 Hz), 8.39 (1H, d, J=4.9 Hz), 8.44 (1H, s),8.53 (1H, s), 9.32 (1H, s).

Example 86N-cyclopropyl-N-methyl-1-(4-(4-methyl-1H-pyrazol-1-yl)pyridin-3-yl)piperidine-4-carboxamide

To a mixture of1-(4-(4-methyl-1H-pyrazol-1-yl)pyridin-3-yl)piperidine-4-carboxylic acid(0.5 g) and DMF (8.2 mL) were added HATU (0.86 g), triethylamine (0.97mL) and N-methylcyclopropanamine (0.15 g), and the mixture was stirredat room temperature for 3 hr. To the mixture was added water, and themixture was extracted with ethyl acetate. The organic layer was washedwith water and saturated brine, and dried over anhydrous magnesiumsulfate, and the solvent was evaporated under reduced pressure. Theresidue was purified by silica gel column chromatography (NH, ethylacetate/hexane), and the obtained solid was crystallized from ethylacetate/hexane to give the title compound (0.25 g).

¹H NMR (300 MHz, CDCl₃) δ 0.68-1.00 (4H, m), 1.77 (2H, s), 1.96 (2H, dd,J=12.3, 2.8 Hz), 2.17 (3H, s), 2.65-2.83 (3H, m), 2.94 (3H, s), 3.14(3H, d, J=11.7 Hz), 7.54 (1H, s), 7.62 (1H, d, J=5.3 Hz), 8.25-8.50 (3H,m).

Example 87(2R)-1-((1-(4-(5-methyl-1,3,4-thiadiazol-2-yl)pyridin-3-yl)piperidin-4-yl)carbonyl)pyrrolidine-2-carbonitrileA) N′-acetyl-3-fluoroisonicotinohydrazide

A mixture of 3-fluoroisonicotine acid (4.5 g) and thionyl chloride (20mL) was heated with reflux under nitrogen atmosphere for 4 hr. Thesolvent was evaporated under reduced pressure. The residue was suspendedin toluene, and the solvent was evaporated under reduced pressure. Theresidue was suspended in THF (20 mL), the suspension was added dropwiseto a mixture of acetohydrazide (2.8 g), triethylamine (9.8 mL) and THF(20 mL) under ice-cooling, and the mixture was stirred at roomtemperature for 30 min. The insoluble substance was removed byfiltration, and the solvent was evaporated under reduced pressure. Theresidue was purified by silica gel column chromatography (methanol/ethylacetate) to give the title compound (3.9 g).

MS (API+): [M+H]⁺ 198.1.

B) 2-(3-fluoropyridin-4-yl)-5-methyl-1,3,4-thiadiazole

To a mixture of N′-acetyl-3-fluoroisonicotinohydrazide (3.8 g) andtoluene (100 mL) was added2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane 2,4-disulfide (7.8g), and the mixture was stirred at 110° C. for 5 hr. The solvent wasevaporated under reduced pressure. The residue was purified by silicagel column chromatography (NH, ethyl acetate/hexane) to give the titlecompound (2.6 g).

MS (API+): [M+H]⁺ 196.1.

C) ethyl1-(4-(5-methyl-1,3,4-thiadiazol-2-yl)pyridin-3-yl)piperidine-4-carboxylate

A mixture of 2-(3-fluoropyridin-4-yl)-5-methyl-1,3,4-thiadiazole (1.5g), ethyl piperidine-4-carboxylate (1.8 g), potassium carbonate (1.6 g)and NMP (8.0 mL) was stirred at 150° C. for 2 hr. The mixture wasallowed to be cooled to room temperature, diluted with water, andextracted with ethyl acetate. The organic layer was washed withsaturated brine, and dried over anhydrous magnesium sulfate, and thesolvent was evaporated under reduced pressure. The residue was purifiedby silica gel column chromatography (NH, ethyl acetate/hexane), and theobtained solid was washed with ethyl acetate/hexane to give the titlecompound (1.5 g).

MS (API+): [M+H]⁺ 333.2.

D)1-(4-(5-methyl-1,3,4-thiadiazol-2-yl)pyridin-3-yl)piperidine-4-carboxylicacid

To a mixture of ethyl1-(4-(5-methyl-1,3,4-thiadiazol-2-yl)pyridin-3-yl)piperidine-4-carboxylate(1.5 g), THF (10 mL) and methanol (3.0 mL) was added 2M aqueous sodiumhydroxide solution (2.2 mL) at room temperature, and the mixture wasstirred overnight. To the mixture was added again 2M aqueous sodiumhydroxide solution (2.2 mL), and the mixture was stirred at roomtemperature for 15 min. The mixture was neutralized with 1M hydrochloricacid, and the obtained solid was collected by filtration to give thetitle compound (1.3 g).

MS (API+): [M+H]⁺ 305.2.

E)(2R)-1-((1-(4-(5-methyl-1,3,4-thiadiazol-2-yl)pyridin-3-yl)piperidin-4-yl)carbonyl)pyrrolidine-2-carbonitrile

To a mixture of1-(4-(5-methyl-1,3,4-thiadiazol-2-yl)pyridin-3-yl)piperidine-4-carboxylicacid (80 mg), DIPEA (0.23 mL) and DMF (0.50 mL) was added HATU (150 mg),and a mixture of (R)-pyrrolidine-2-carbonitrile hydrochloride (52 mg)and DMF (0.50 mL) was added thereto, and the mixture was stirredovernight at room temperature. The mixture was diluted with water, andextracted with ethyl acetate. The organic layer was washed withsaturated brine, and dried over anhydrous magnesium sulfate, and thesolvent was evaporated under reduced pressure. The residue was purifiedby silica gel column chromatography (NH, ethyl acetate/hexane), and theobtained solid was recrystallized from ethyl acetate/hexane to give thetitle compound (59 mg).

¹H NMR (300 MHz, CDCl₃) δ 1.77-2.01 (2H, m), 2.07-2.41 (6H, m),2.45-2.63 (1H, m), 2.80-2.88 (3H, m), 2.89-3.08 (2H, m), 3.18 (2H, d,J=3.4 Hz), 3.44-3.65 (1H, m), 3.68-3.81 (1H, m), 4.66-4.85 (1H, m), 8.20(1H, d, J=5.7 Hz), 8.53 (1H, d, J=4.9 Hz), 8.60-8.68 (1H, m).

Example 1141-((1-(4-(4-methyl-1H-pyrazol-1-yl)pyridin-3-yl)piperidin-4-yl)carbonyl)-L-prolinamide

To a mixture of1-(4-(4-methyl-1H-pyrazol-1-yl)pyridin-3-yl)piperidine-4-carboxylic acid(100 mg), DIPEA (0.31 mL) and DMF (2.0 mL) were added HATU (200 mg) and(S)-pyrrolidine-2-carboxamide (48 mg), and the mixture was stirred atroom temperature for 30 min. The mixture was diluted with water andsaturated brine, and extracted with ethyl acetate/THF. The organic layerwas washed with saturated brine, and dried over anhydrous magnesiumsulfate, and the solvent was evaporated under reduced pressure. Theresidue was purified by silica gel column chromatography (NH,methanol/ethyl acetate) to give the title compound (92 mg).

¹H NMR (300 MHz, CDCl₃) δ 1.74-2.23 (10H, m), 2.36-2.58 (2H, m),2.65-2.82 (2H, m), 3.05-3.23 (2H, m), 3.49-3.72 (2H, m), 4.61 (1H, dd,J=8.1, 2.1 Hz), 5.28 (1H, brs), 6.88 (1H, brs), 7.54 (1H, s), 7.58-7.63(1H, m), 8.30-8.37 (2H, m), 8.37-8.42 (1H, m).

Example 1184,4-difluoro-1-((1-(4-(4-methyl-1H-pyrazol-1-yl)pyridin-3-yl)piperidin-4-yl)carbonyl)-L-prolinamide

To a mixture of1-(4-(4-methyl-1H-pyrazol-1-yl)pyridin-3-yl)piperidine-4-carboxylic acid(300 mg) and DMF (6.0 mL) were added HATU (520 mg), triethylamine (0.32mL) and (S)-4,4-difluoropyrrolidine-2-carboxamide (240 mg) at roomtemperature, and the mixture was stirred for 1 hr. To the mixture wasadded water, and the mixture was extracted with ethyl acetate. Theorganic layer was washed with water and saturated brine, and dried overanhydrous sodium sulfate, and the solvent was evaporated under reducedpressure. The residue was purified by silica gel column chromatography(NH, ethyl acetate/hexane), and a part (53 mg) of the obtained solid waswashed with ether to give the title compound (39 mg).

¹H NMR (300 MHz, DMSO-d₆) δ 1.56-1.85 (4H, m), 2.12 (3H, s), 2.25-2.37(1H, m), 2.62-2.80 (3H, m), 2.88-3.04 (3H, m), 3.86-4.24 (2H, m), 4.44(1H, dd, J=9.5, 4.9 Hz), 7.07 (1H, s), 7.38 (1H, brs), 7.53 (1H, d,J=5.3 Hz), 7.63 (1H, s), 8.31 (1H, d, J=4.9 Hz), 8.40 (1H, s), 8.43 (1H,s).

Example 120(2S)-1-((1-(4-(4-methyl-1H-pyrazol-1-yl)pyridin-3-yl)piperidin-4-yl)carbonyl)pyrrolidine-2-carbonitrile

To a mixture of1-(4-(4-methyl-1H-pyrazol-1-yl)pyridin-3-yl)piperidine-4-carboxylic acid(100 mg), DIPEA (0.31 mL) and DMF (2.0 mL) were added HATU (200 mg) and(S)-pyrrolidine-2-carbonitrile hydrochloride (56 mg), and the mixturewas stirred at room temperature for 30 min. The mixture was diluted withwater and saturated brine, and extracted with ethyl acetate/THF. Theorganic layer was washed with saturated brine, and dried over anhydrousmagnesium sulfate, and the solvent was evaporated under reducedpressure. The residue was purified by silica gel column chromatography(NH, ethyl acetate/hexane), and the obtained solid was recrystallizedfrom ethyl acetate/hexane to give the title compound (86 mg).

¹H NMR (300 MHz, CDCl₃) δ 1.70-2.05 (4H, m), 2.10-2.60 (8H, m),2.62-2.88 (2H, m), 3.02-3.27 (2H, m), 3.44-3.60 (1H, m), 3.64-3.77 (1H,m), 4.59-4.88 (1H, m), 7.54 (1H, s), 7.61 (1H, d, J=5.3 Hz), 8.30-8.38(2H, m), 8.40 (1H, s).

Example 121(2S)-4,4-difluoro-1-((1-(4-(4-methyl-1H-pyrazol-1-yl)pyridin-3-yl)piperidin-4-yl)carbonyl)pyrrolidine-2-carbonitrile

To a mixture of4,4-difluoro-1-((1-(4-(4-methyl-1H-pyrazol-1-yl)pyridin-3-yl)piperidin-4-yl)carbonyl)-L-prolinamide(380 mg), imidazole (62 mg) and pyridine (4.5 mL) was added phosphorusoxychloride (0.17 mL) at −40° C., and the mixture was stirred at −20° C.for 1 hr. To the mixture was added 1M hydrochloric acid (30 mL), and themixture was extracted with ethyl acetate. The organic layer was washedwith water and saturated brine, and dried over anhydrous sodium sulfate,and the solvent was evaporated under reduced pressure. The residue waspurified by silica gel column chromatography (NH, ethyl acetate/hexane)to give the title compound (290 mg).

¹H NMR (300 MHz, DMSO-d₆) δ 1.52-1.85 (4H, m), 2.12 (3H, s), 2.61-3.06(6H, m), 3.92-4.32 (3H, m), 5.04 (1H, dd, J=9.1, 3.0 Hz), 7.53 (1H, d,J=5.3 Hz), 7.63 (1H, s), 8.31 (1H, d, J=4.9 Hz), 8.42 (2H, d, J=6.8 Hz).

Example 1241-((1-(4-(4-methyl-1H-pyrazol-1-yl)pyridin-3-yl)piperidin-4-yl)carbonyl)-D-prolinamide

To a mixture of1-(4-(4-methyl-1H-pyrazol-1-yl)pyridin-3-yl)piperidine-4-carboxylic acid(52 mg) and DMF (1.0 mL) were added HATU (90 mg), triethylamine (0.056mL) and (R)-prolinamide (25 mg) at room temperature, and the mixture wasstirred for 2 hr. To the mixture was added water, and the mixture wasextracted with ethyl acetate. The organic layer was washed withsaturated brine, and dried over anhydrous sodium sulfate, and thesolvent was evaporated under reduced pressure. The residue was purifiedby silica gel column chromatography (NH, ethyl acetate/hexane andmethanol/ethyl acetate) to give the title compound (62 mg).

¹H NMR (300 MHz, DMSO-d₆) δ 1.58-1.98 (8H, m), 2.12 (3H, s), 2.62-2.81(2H, m), 2.87-3.04 (2H, m), 3.40-3.67 (2H, m), 4.15-4.39 (1H, m), 5.74(1H, s), 6.84 (1H, s), 7.12-7.23 (1H, m), 7.50-7.56 (1H, m), 7.63 (1H,s), 8.30 (1H, d, J=5.3 Hz), 8.39-8.46 (2H, m).

Example 1252-methyl-1-((1-(4-(4-methyl-1H-pyrazol-1-yl)pyridin-3-yl)piperidin-4-yl)carbonyl)-D-prolinamideA) (R)-methyl 2-methylpyrrolidine-2-carboxylate hydrochloride

To a mixture of (R)-2-methylpyrrolidine-2-carboxylic acid (400 mg) andmethanol (10 mL) was added dropwise thionyl chloride (0.68 mL) underice-cooling, and the mixture was stirred overnight at room temperature.The solvent was evaporated under reduced pressure. The residue wassuspended in ethyl acetate, and the obtained solid was collected byfiltration to give the title compound (400 mg).

¹H NMR (300 MHz, CDCl₃) δ 1.86 (3H, s), 1.93-2.25 (3H, m), 2.33-2.53(1H, m), 3.48-3.69 (2H, m), 3.86 (3H, s), 9.47 (1H, brs), 10.48 (1H,brs).

B) (R)-methyl2-methyl-1-(1-(4-(4-methyl-1H-pyrazol-1-yl)pyridin-3-yl)piperidine-4-carbonyl)pyrrolidine-2-carboxylate

To a mixture of1-(4-(4-methyl-1H-pyrazol-1-yl)pyridin-3-yl)piperidine-4-carboxylic acid(200 mg), (R)-methyl 2-methylpyrrolidine-2-carboxylate hydrochloride(150 mg) and DMF (3.0 mL) were added HATU (400 mg) and DIPEA (0.61 mL),and the mixture was stirred overnight at room temperature. The mixturewas diluted with water, and extracted with ethyl acetate. The organiclayer was washed with saturated brine, and dried over anhydrousmagnesium sulfate, and the solvent was evaporated under reducedpressure. The residue was purified by silica gel column chromatography(NH, ethyl acetate/hexane) to give the title compound (190 mg).

MS (API+): [M+H]⁺ 412.3.

C)(R)-2-methyl-1-(1-(4-(4-methyl-1H-pyrazol-1-yl)pyridin-3-yl)piperidine-4-carbonyl)pyrrolidine-2-carboxylicacid

To a mixture of (R)-methyl2-methyl-1-(1-(4-(4-methyl-1H-pyrazol-1-yl)pyridin-3-yl)piperidine-4-carbonyl)pyrrolidine-2-carboxylate(160 mg), THF (1.0 mL) and methanol (0.30 mL) was added 2M aqueoussodium hydroxide solution (0.39 mL), and the mixture was stirred at roomtemperature for 3 hr, and then overnight at 50° C. The mixture wasacidified (pH-4) with 1M hydrochloric acid, diluted with saturatedbrine, and extracted with ethyl acetate/THF. The organic layer waswashed with saturated brine, and dried over anhydrous magnesium sulfate,and the solvent was evaporated under reduced pressure to give the titlecompound (160 mg).

MS (API+): [M+H]⁺ 398.2.

D)2-methyl-1-((1-(4-(4-methyl-1H-pyrazol-1-yl)pyridin-3-yl)piperidin-4-yl)carbonyl)-D-prolinamide

To a mixture of(R)-2-methyl-1-(1-(4-(4-methyl-1H-pyrazol-1-yl)pyridin-3-yl)piperidine-4-carbonyl)pyrrolidine-2-carboxylicacid (160 mg), DIPEA (0.11 mL) and DMF (2.0 mL) was added HATU (230 mg),and the mixture was stirred at room temperature for 30 min. To themixture was added 0.4M ammonia/THF solution (1.5 mL), and the mixturewas stirred overnight at room temperature. The mixture was diluted withwater, saturated aqueous sodium bicarbonate solution and saturatedbrine, and extracted with ethyl acetate. The organic layer was washedwith saturated brine, and dried over anhydrous magnesium sulfate, andthe solvent was evaporated under reduced pressure. The residue waspurified by silica gel column chromatography (NH, methanol/ethylacetate) to give the title compound (110 mg).

¹H NMR (300 MHz, CDCl₃) δ 1.68 (3H, s), 1.70-2.03 (7H, m), 2.17 (3H, s),2.43-2.79 (4H, m), 3.09-3.21 (2H, m), 3.55-3.77 (2H, m), 5.25 (1H, brs),6.91 (1H, s), 7.54 (1H, s), 7.61 (1H, d, J=5.3 Hz), 8.31-8.38 (2H, m),8.40 (1H, s).

Example 1262-methyl-1-((1-(4-(5-methyl-1,3,4-thiadiazol-2-yl)pyridin-3-yl)piperidin-4-yl)carbonyl)-D-prolinamideA) (R)-methyl2-methyl-1-(1-(4-(5-methyl-1,3,4-thiadiazol-2-yl)pyridin-3-yl)piperidine-4-carbonyl)pyrrolidine-2-carboxylate

To a mixture of1-(4-(5-methyl-1,3,4-thiadiazol-2-yl)pyridin-3-yl)piperidine-4-carboxylicacid (200 mg), (R)-methyl 2-methylpyrrolidine-2-carboxylatehydrochloride (130 mg) and DMF (3.0 mL) were added HATU (380 mg) andDIPEA (0.57 mL), and the mixture was stirred overnight at roomtemperature. The mixture was diluted with water, and extracted withethyl acetate. The organic layer was washed with saturated brine, anddried over anhydrous magnesium sulfate, and the solvent was evaporatedunder reduced pressure. The residue was purified by silica gel columnchromatography (NH, ethyl acetate/hexane) to give the title compound(250 mg).

MS (API+): [M+H]⁺ 430.1.

B)(R)-2-methyl-1-(1-(4-(5-methyl-1,3,4-thiadiazol-2-yl)pyridin-3-yl)piperidine-4-carbonyl)pyrrolidine-2-carboxylicacid

To a mixture of (R)-methyl2-methyl-1-(1-(4-(5-methyl-1,3,4-thiadiazol-2-yl)pyridin-3-yl)piperidine-4-carbonyl)pyrrolidine-2-carboxylate(250 mg), THF (1.5 mL) and methanol (0.50 mL) was added 2M aqueoussodium hydroxide solution (1.1 mL), and the mixture was heated withreflux for 2 hr. The mixture was acidified (pH-4 to 5) with 1Mhydrochloric acid, diluted with saturated brine, and extracted withethyl acetate/THF. The organic layer was washed with saturated brine,and dried over anhydrous magnesium sulfate, and the solvent wasevaporated under reduced pressure to give the title compound (230 mg).

MS (API+): [M+H]⁺ 416.2.

C)2-methyl-1-((1-(4-(5-methyl-1,3,4-thiadiazol-2-yl)pyridin-3-yl)piperidin-4-yl)carbonyl)-D-prolinamide

To a mixture of(R)-2-methyl-1-(1-(4-(5-methyl-1,3,4-thiadiazol-2-yl)pyridin-3-yl)piperidine-4-carbonyl)pyrrolidine-2-carboxylicacid (220 mg), DIPEA (0.14 mL) and DMF (2.0 mL) was added HATU (300 mg),and the mixture was stirred at room temperature for 1 hr under nitrogenatmosphere. To the mixture was added 0.4 M ammonia/THF solution (2.0mL), and the mixture was stirred overnight at room temperature. Themixture was diluted with saturated brine, and extracted with ethylacetate/THF. The organic layer was washed with saturated brine, anddried over anhydrous magnesium sulfate, and the solvent was evaporatedunder reduced pressure. The residue was purified by silica gel columnchromatography (NH, methanol/ethyl acetate) to give the title compound(160 mg).

¹H NMR (300 MHz, CDCl₃) δ 1.71 (3H, s), 1.73-2.23 (7H, m), 2.49-2.68(2H, m), 2.84 (3H, s), 2.89-3.01 (2H, m), 3.11-3.22 (2H, m), 3.60-3.81(2H, m), 5.29 (1H, brs), 6.83 (1H, brs), 8.20 (1H, d, J=5.3 Hz), 8.52(1H, d, J=5.3 Hz), 8.65 (1H, s).

Example 127(2R)-2-methyl-1-((1-(4-(4-methyl-1H-pyrazol-1-yl)pyridin-3-yl)piperidin-4-yl)carbonyl)pyrrolidine-2-carbonitrile

To a mixture of2-methyl-1-((1-(4-(4-methyl-1H-pyrazol-1-yl)pyridin-3-yl)piperidin-4-yl)carbonyl)-D-prolinamide(100 mg) and pyridine (2.0 mL) was added trifluoroacetic anhydride(0.039 mL) under ice-cooling, and the mixture was stirred at roomtemperature for 30 min. To the mixture was added again trifluoroaceticanhydride (0.039 mL) under ice-cooling, and the mixture was stirred atroom temperature for 30 min. To the mixture was added trifluoroaceticanhydride (0.078 mL), and the mixture was stirred at room temperaturefor 30 min. To the mixture was added water, and the mixture wasextracted with ethyl acetate. The organic layer was washed withsaturated brine, and dried over anhydrous magnesium sulfate, and thesolvent was evaporated under reduced pressure. The residue was purifiedby silica gel column chromatography (NH, ethyl acetate/hexane) to givethe title compound (76 mg).

¹H NMR (300 MHz, CDCl₃) δ 1.76 (3H, s), 1.80-2.14 (7H, m), 2.18 (3H, s),2.36-2.60 (2H, m), 2.71 (2H, t, J=11.7 Hz), 3.07-3.24 (2H, m), 3.53-3.76(2H, m), 7.54 (1H, s), 7.61 (1H, d, J=5.3 Hz), 8.31-8.36 (2H, m), 8.40(1H, s).

Example 128(2R)-2-methyl-1-((1-(4-(5-methyl-1,3,4-thiadiazol-2-yl)pyridin-3-yl)piperidin-4-yl)carbonyl)pyrrolidine-2-carbonitrile

To a mixture of2-methyl-1-((1-(4-(5-methyl-1,3,4-thiadiazol-2-yl)pyridin-3-yl)piperidin-4-yl)carbonyl)-D-prolinamide(160 mg) and pyridine (2.0 mL) was added trifluoroacetic anhydride (0.12mL) under ice-cooling, and the mixture was stirred under nitrogenatmosphere, under ice-cooling for 15 min. To the mixture was addedsaturated aqueous sodium bicarbonate solution under ice-cooling, and themixture was diluted with saturated brine, and extracted with ethylacetate. The organic layer was washed with saturated brine, and driedover anhydrous magnesium sulfate, and the solvent was evaporated underreduced pressure. The residue was purified by silica gel columnchromatography (NH, ethyl acetate/hexane), and the obtained solid wasrecrystallized from ethyl acetate/hexane to give the title compound (87mg).

¹H NMR (300 MHz, CDCl₃) δ 1.78 (3H, s), 1.82-1.97 (2H, m), 2.03-2.28(5H, m), 2.44-2.61 (2H, m), 2.86 (3H, s), 2.93 (2H, tt, J=11.9, 2.5 Hz),3.11-3.22 (2H, m, J=5.9, 3.6 Hz), 3.59-3.79 (2H, m), 8.20 (1H, d, J=4.5Hz), 8.53 (1H, d, J=4.9 Hz), 8.64 (1H, s).

Example 129(2R)-1-((1-(4-(5-methyl-1,3-thiazol-2-yl)pyridin-3-yl)piperidin-4-yl)carbonyl)pyrrolidine-2-carbonitrileA) 3-fluoro-N-(2-hydroxypropyl)isonicotinamide

A mixture of 3-fluoroisonicotine acid (4.5 g) and thionyl chloride (20mL) was heated with reflux under nitrogen atmosphere for 4 hr. Themixture was concentrated under reduced pressure, and to the residue wasadded anhydrous THF (20 mL). To the mixture was added dropwise a mixtureof 1-aminopropan-2-ol (2.9 g), DIPEA (12 mL) and THF (20 mL) at 0° C.,and the mixture was stirred overnight at room temperature. The mixturewas concentrated under reduced pressure, and to the residue was addedTHF. The insoluble substance was removed by filtration, and the filtratewas concentrated under reduced pressure. The residue was purified bysilica gel column chromatography (methanol/ethyl acetate) to give thetitle compound (4.9 g).

MS (API+): [M+H]⁺ 199.1.

B) 3-fluoro-N-(2-oxopropyl)isonicotinamide

To a mixture of 3-fluoro-N-(2-hydroxypropyl)isonicotinamide (4.4 g),triethylamine (6.2 mL) and DMSO (70 mL) was added sulfur trioxidecomplex (7.0 g) at room temperature, and the mixture was stirredovernight. The mixture was concentrated under reduced pressure, and tothe residue were added water and ethyl acetate. The mixture was basifiedwith 1M aqueous sodium hydroxide solution, and extracted with ethylacetate and THF. The organic layer was washed with saturated brine, anddried over anhydrous magnesium sulfate, and the solvent was evaporatedunder reduced pressure. The residue was purified by silica gel columnchromatography (ethyl acetate/hexane) to give the title compound (1.9g).

MS (API+): [M+H]⁺ 197.2.

C) 2-(3-fluoropyridin-4-yl)-5-methylthiazole

To a mixture of 3-fluoro-N-(2-oxopropyl)isonicotinamide (1.9 g) andtoluene (30 mL) was added 2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane 2,4-disulfide (4.7 g), and the mixture wasstirred at 110° C. for 1 hr. The mixture was concentrated under reducedpressure, and the residue was purified by silica gel columnchromatography (NH, ethyl acetate/hexane) to give the title compound(1.0 g).

MS (API+): [M+H]⁺ 195.1.

D) ethyl1-(4-(5-methylthiazol-2-yl)pyridin-3-yl)piperidine-4-carboxylate

A mixture of 2-(3-fluoropyridin-4-yl)-5-methylthiazole (500 mg), ethylpiperidine-4-carboxylate (610 mg), potassium carbonate (530 mg) and NMP(2.0 mL) was stirred overnight at 150° C. The mixture was allowed to becooled to room temperature, and ethyl piperidine-4-carboxylate (2.0 mL)was added thereto. The mixture was stirred at 180° C. for 2 hr, and thenovernight at room temperature. The mixture was allowed to be cooled toroom temperature, water was added thereto, and the mixture was extractedwith ethyl acetate. The organic layer was washed with saturated brine,and dried over anhydrous magnesium sulfate, and the solvent wasevaporated under reduced pressure. The residue was purified by silicagel column chromatography (ethyl acetate/hexane) to give the titlecompound (780 mg).

MS (API+): [M+H]⁺ 332.2.

E) 1-(4-(5-methylthiazol-2-yl)pyridin-3-yl)piperidine-4-carboxylic acid

Ethyl 1-(4-(5-methylthiazol-2-yl)pyridin-3-yl)piperidine-4-carboxylate(770 mg) was dissolved in THF (5.0 mL) and methanol (2.0 mL), to thesolution was added 2M aqueous sodium hydroxide solution (2.3 mL), andthe mixture was stirred at room temperature for 2 hr. The mixture wasneutralized with 1M hydrochloric acid (4.7 mL), and the precipitatedsolid was collected by filtration to give the title compound (480 mg).

MS (API+): [M+H]₊ 304.1.

F)(2R)-1-((1-(4-(5-methyl-1,3-thiazol-2-yl)pyridin-3-yl)piperidin-4-yl)carbonyl)pyrrolidine-2-carbonitrile

To a mixture of1-(4-(b-methylthiazol-2-yl)pyridin-3-yl)piperidine-4-carboxylic acid andDMF (1.0 mL) were added HATU (86 mg), triethylamine (0.053 mL) and(R)-pyrrolidine-2-carbonitrile hydrochloride (28 mg) at roomtemperature, and the mixture was stirred for 2 hr. To the mixture wasadded water, and the mixture was extracted with ethyl acetate. Theorganic layer was washed with water and saturated brine, and dried overanhydrous sodium sulfate, and the solvent was evaporated under reducedpressure. The residue was purified by silica gel column chromatography(NH, ethyl acetate/hexane), and the obtained solid was crystallized fromethyl acetate/hexane to give the title compound (39 mg).

¹H NMR (300 MHz, DMSO-d₆) δ 1.75-2.30 (8H, m), 2.53 (3H, d, J=0.8 Hz),2.61-2.75 (1H, m), 2.91-3.11 (4H, m), 3.52-3.63 (1H, m), 3.68-3.78 (1H,m), 4.75 (1H, dd, J=7.2, 3.8 Hz), 7.72 (1H, d, J=1.1 Hz), 8.03 (1H, d,J=5.3 Hz), 8.44 (1H, d, J=5.3 Hz), 8.68 (1H, s).

Example 130(2R)-4,4-difluoro-1-((1-(4-(4-methyl-1H-pyrazol-1-yl)pyridin-3-yl)piperidin-4-yl)carbonyl)pyrrolidine-2-carbonitrileA) (2R,4R)-1-(tert-butoxycarbonyl)-4-hydroxypyrrolidine-2-carboxylicacid

A mixture of (2R,4R)-4-hydroxypyrrolidine-2-carboxylic acid (5.3 g),di-tert-butyl dicarbonate (19 mL), triethylamine (10 mL) and methanol(90 mL) was heated with reflux for 2 hr. The mixture was allowed to becooled to room temperature, and the solvent was evaporated under reducedpressure. The residue was adjusted to pH2 with sodiumdihydrogenphosphate (400 mg) and dilute hydrochloric acid underice-cooling. The mixture was stirred under ice-cooling for 30 min, andextracted with ethyl acetate/2-propanol (5:1). The organic layer wasseparated, washed with saturated brine, and dried over magnesiumsulfate, and the solvent was evaporated under reduced pressure to givethe title compound (9.3 g).

¹H NMR (300 MHz, DMSO-d₆) δ 1.31-1.41 (9H, m), 1.75-1.86 (1H, m),2.23-2.39 (1H, m), 3.03-3.15 (1H, m), 3.43-3.54 (1H, m), 4.03-4.13 (1H,m), 4.15-4.25 (1H, m).

B) (2R,4R)-tert-butyl 2-carbamoyl-4-hydroxypyrrolidine-1-carboxylate

To a mixture of(2R,4R)-1-(tert-butoxycarbonyl)-4-hydroxypyrrolidine-2-carboxylic acid(500 mg) and acetonitrile (6.0 mL) were added WSC hydrochloride (500 mg)and HOBt monohydrate (400 mg) under ice-cooling. The mixture was stirredat room temperature for 1.5 hr, and cooled to 0° C., and 28% aqueousammonia (0.60 mL) was added thereto. The mixture was stirred at the sametemperature for 15 min, and then at room temperature for 30 min. To themixture was added sodium sulfate, the insoluble substance was removedthrough silica gel (NH, ethyl acetate), and the filtrate wasconcentrated under reduced pressure. The residue was purified by silicagel column chromatography (methanol/ethyl acetate) to give the titlecompound (320 mg).

¹H NMR (400 MHz, DMSO-d₆) δ 1.30-1.43 (9H, m), 1.65-1.75 (1H, m),2.21-2.35 (1H, m), 3.13-3.22 (1H, m), 3.41-3.50 (1H, m), 3.97-4.17 (2H,m), 5.25 (1H, d, J=6.8 Hz), 7.04-7.16 (1H, m), 7.39-7.49 (1H, m).

C) (R)-tert-butyl 2-carbamoyl-4-oxopyrrolidine-1-carboxylate

To a mixture of (2R,4R)-tert-butyl2-carbamoyl-4-hydroxypyrrolidine-1-carboxylate (4.0 g) and ethyl acetate(40 mL)/water (40 mL) were added ruthenium(IV) oxide monohydrate (0.13g) and sodium periodate (11 g) under ice-cooling. The mixture wasstirred at room temperature for 4 hr, and extracted with ethylacetate/2-propanol (5:1). The organic layer was washed with water andsaturated brine, and dried over magnesium sulfate, and the solvent wasevaporated under reduced pressure. The residue was purified by silicagel column chromatography (ethyl acetate/hexane) to give the titlecompound (2.4 g).

¹H NMR (300 MHz, DMSO-d₆) δ 1.36-1.44 (9H, m), 2.24-2.37 (1H, m),2.93-3.12 (1H, m), 3.63-3.85 (2H, m), 4.44-4.58 (1H, m), 7.04-7.21 (1H,m), 7.58 (1H, brs).

D) (R)-tert-butyl 2-carbamoyl-4,4-difluoropyrrolidine-1-carboxylate

To a mixture of (R)-tert-butyl2-carbamoyl-4-oxopyrrolidine-1-carboxylate (2.4 g) and dichloromethane(50 mL) was added bis(2-methoxyethyl)aminosulfur trifluoride (5.8 mL) at−5° C. The mixture was stirred at the same temperature for 15 min, andthen at room temperature for 3.5 hr. The mixture was poured into sodiumbicarbonate and ice, stirred for 40 min, and extracted with ethylacetate. The organic layer was washed with water and saturated brine,and dried over sodium sulfate, and the solvent was evaporated underreduced pressure. The residue was purified by silica gel columnchromatography (ethyl acetate/hexane) to give the title compound (1.4g).

¹H NMR (300 MHz, DMSO-d₆) δ 1.30-1.46 (9H, m), 2.20-2.42 (1H, m),2.65-2.88 (1H, m), 3.61-3.83 (2H, m), 4.19-4.32 (1H, m), 7.05-7.19 (1H,m), 7.40-7.53 (1H, m).

E) (R)-tert-butyl 2-cyano-4,4-difluoropyrrolidine-1-carboxylate

To a mixture of (R)-tert-butyl2-carbamoyl-4,4-difluoropyrrolidine-1-carboxylate (1.1 g) and pyridine(10 mL) was added trifluoroacetic anhydride (0.79 mL) at −5° C. Themixture was stirred at the same temperature for 15 min, and then at roomtemperature for 1 hr. The mixture was diluted with ethyl acetate/water,and extracted with ethyl acetate. The organic layer was washed withwater and saturated brine, and dried over magnesium sulfate, and thesolvent was evaporated under reduced pressure. The residue was purifiedby silica gel column chromatography (ethyl acetate/hexane) to give thetitle compound (0.82 g).

¹H NMR (300 MHz, DMSO-d₆) δ 1.45 (9H, s), 2.67-3.01 (2H, m), 3.63-3.87(2H, m), 4.96 (1H, dd, J=9.1, 2.7 Hz).

F) (R)-4,4-difluoropyrrolidine-2-carbonitrile 4-methylbenzenesulfonate

A mixture of (R)-tert-butyl2-cyano-4,4-difluoropyrrolidine-1-carboxylate (0.82 g),p-toluenesulfonic acid monohydrate (1.3 g) and acetonitrile (15 mL) wasstirred at room temperature for 18 hr. The solvent was evaporated underreduced pressure, the residue was dissolved in ethyl acetate, and thesolution was concentrated again under reduced pressure. To the resultingsolid were added successively diethyl ether and ethyl acetate, and theprecipitate was collected by filtration, and washed with cooled ethylacetate to give the title compound (0.67 g).

¹H NMR (300 MHz, CD₃OD) δ 2.37 (3H, s), 2.81-3.13 (2H, m), 3.71-3.95(2H, m), 5.02-5.11 (1H, m), 7.23 (2H, d, J=8.0 Hz), 7.68-7.74 (2H, m).

G)(2R)-4,4-difluoro-1-((1-(4-(4-methyl-1H-pyrazol-1-yl)pyridin-3-yl)piperidin-4-yl)carbonyl)pyrrolidine-2-carbonitrile

A mixture of1-(4-(4-methyl-1H-pyrazol-1-yl)pyridin-3-yl)piperidine-4-carboxylic acid(60 mg), (R)-4,4-difluoropyrrolidine-2-carbonitrile4-methylbenzenesulfonate (96 mg), HATU (110 mg), DIPEA (0.11 mL) and DMF(2.0 mL) was stirred at room temperature for 18 hr. The mixture wasdiluted with ethyl acetate/water, and extracted with ethyl acetate. Theorganic layer was washed with water and saturated brine, and dried oversodium sulfate, and the solvent was evaporated under reduced pressure.The residue was purified by silica gel column chromatography (NH, ethylacetate/hexane) to give the title compound (70 mg).

¹H NMR (300 MHz, DMSO-d₆) δ 1.60-1.84 (4H, m), 2.12 (3H, s), 2.54-3.04(7H, m), 4.04-4.30 (2H, m), 5.04 (1H, dd, J=9.3, 3.2 Hz), 7.53 (1H, d,J=5.3 Hz), 7.63 (1H, s), 8.31 (1H, d, J=4.9 Hz), 8.39-8.44 (2H, m).

Example 131(2R)-1-((4-fluoro-1-(4-(5-methyl-1,3,4-thiadiazol-2-yl)pyridin-3-yl)piperidin-4-yl)carbonyl)pyrrolidine-2-carbonitrileA) ethyl4-fluoro-1-(4-(5-methyl-1,3,4-thiadiazol-2-yl)pyridin-3-yl)piperidine-4-carboxylate

A mixture of 2-(3-fluoropyridin-4-yl)-5-methyl-1,3,4-thiadiazole (300mg), ethyl 4-fluoropiperidine-4-carboxylate (650 mg), potassiumcarbonate (320 mg) and NMP (1.0 mL) was stirred with microwaveirradiation at 180° C. for 1 hr. The mixture was diluted with water, andextracted with ethyl acetate. The organic layer was washed withsaturated brine, and dried over anhydrous magnesium sulfate, and thesolvent was evaporated under reduced pressure. The residue was purifiedby silica gel column chromatography (NH, ethyl acetate/hexane) to givethe title compound (130 mg).

MS (API+): [M+H]⁺ 351.1.

B)(2R)-1-((4-fluoro-1-(4-(5-methyl-1,3,4-thiadiazol-2-yl)pyridin-3-yl)piperidin-4-yl)carbonyl)pyrrolidine-2-carbonitrile

To a mixture of ethyl4-fluoro-1-(4-(5-methyl-1,3,4-thiadiazol-2-yl)pyridin-3-yl)piperidine-4-carboxylate(120 mg), THF (1.0 mL) and methanol (0.30 mL) was added 2M aqueoussodium hydroxide solution (0.35 mL) at room temperature, and the mixturewas stirred at room temperature for 4 hr. The mixture was acidified(pH=4) with 1M hydrochloric acid, and extracted with ethylacetate/THF/2-propanol, and the solvent was evaporated under reducedpressure. The residue was suspended in toluene, and the solvent wasevaporated under reduced pressure. The obtained solid was washed withethyl acetate. To a mixture of the obtained solid,(R)-pyrrolidine-2-carbonitrile hydrochloride (56 mg) and DMF (1.0 mL)were added HATU (160 mg) and DIPEA (0.19 mL), and the mixture wasstirred overnight at room temperature. The mixture was diluted withsaturated brine, and extracted with ethyl acetate. The organic layer wasdried over anhydrous magnesium sulfate, and the solvent was evaporatedunder reduced pressure. The residue was purified by silica gel columnchromatography (NH, ethyl acetate/hexane), and the obtained solid wasrecrystallized from ethyl acetate/hexane to give the title compound (20mg).

¹H NMR (300 MHz, CDCl₃) δ 1.96-2.76 (8H, m), 2.80-2.91 (3H, m),2.96-3.11 (2H, m), 3.17-3.39 (2H, m), 3.47-4.03 (2H, m), 4.70-5.21 (1H,m), 8.21 (1H, d, J=5.3 Hz), 8.55 (1H, d, J=5.3 Hz), 8.70 (1H, s).

Example 132(2R)-4,4-difluoro-1-((1-(4-(5-methyl-1,3,4-thiadiazol-2-yl)pyridin-3-yl)piperidin-4-yl)carbonyl)pyrrolidine-2-carbonitrile

To a mixture of1-(4-(5-methyl-1,3,4-thiadiazol-2-yl)pyridin-3-yl)piperidine-4-carboxylicacid (60 mg), (R)-4,4-difluoropyrrolidine-2-carbonitrile4-methylbenzenesulfonate (54 mg) and DMF (1 mL) were added HATU (100 mg)and DIPEA (0.12 mL), and the mixture was stirred overnight at roomtemperature. The mixture was diluted with saturated brine, and extractedwith ethyl acetate/THF. The organic layer was dried over anhydrousmagnesium sulfate, and the solvent was evaporated under reducedpressure. The residue was purified by silica gel column chromatography(NH, ethyl acetate/hexane), and the obtained solid was recrystallizedfrom ethyl acetate/hexane to give the title compound (41 mg).

¹H NMR (300 MHz, CDCl₃) δ 1.80-1.99 (2H, m), 2.08-2.28 (2H, m),2.37-2.56 (1H, m), 2.72-2.84 (2H, m), 2.86 (3H, s), 2.95 (2H, td,J=11.9, 2.7 Hz), 3.12-3.25 (2H, m), 3.92-4.11 (2H, m), 5.00 (1H, t,J=6.6 Hz), 8.21 (1H, d, J=4.9 Hz), 8.54 (1H, d, J=5.3 Hz), 8.64 (1H, s).

Example 133 ((2R)-2-(methoxymethyl)pyrrolidin-1-yl)(1-(4-(5-methyl-1, 3,4-thiadiazol-2-yl)pyridin-3-yl)piperidin-4-yl)methanone

To a mixture of1-(4-(5-methyl-1,3,4-thiadiazol-2-yl)pyridin-3-yl)piperidine-4-carboxylicacid (80 mg), (R)-2-(methoxymethyl)pyrrolidine (36 mg) and DMF (1.0 mL)were added HATU (150 mg) and DIPEA (0.14 mL), and the mixture wasstirred at room temperature for 3 hr. The mixture was diluted withwater, and extracted with ethyl acetate. The organic layer was washedwith saturated brine, and dried over anhydrous magnesium sulfate, andthe solvent was evaporated under reduced pressure. The residue waspurified by silica gel column chromatography (NH, ethyl acetate/hexane),and the obtained solid was recrystallized from ethyl acetate/hexane togive the title compound (76 mg).

¹H NMR (300 MHz, CDCl₃) δ 1.73-2.38 (8H, m), 2.46-2.81 (1H, m), 2.84(3H, s), 2.94 (2H, t, J=12.1 Hz), 3.08-3.22 (2H, m), 3.27-3.67 (7H, m),4.08-4.36 (1H, m), 8.20 (1H, d, J=5.3 Hz), 8.52 (1H, d, J=5.3 Hz), 8.64(1H, s).

Example 142(2R)-1-((1-(2,4′-bipyridine-3′-yl)piperidin-4-yl)carbonyl)pyrrolidine-2-carbonitrileA) 1,3-dimethyl-2,3-dihydro-2-oxopyridinium sulfate

To a mixture of 1,3-dimethylurea (40 g), 1,1,3,3-tetramethoxypropane (55mL) and methanol (400 mL) was added dropwise slowly conc. sulfuric acid(27 mL) at room temperature, and the mixture was stirred at 50° C. for30 min. The mixture was cooled to 5° C., and the precipitate wascollected by filtration, and washed with methanol to give the titlecompound (31 g).

¹H NMR (300 MHz, DMSO-d₆) δ 3.71 (6H, s), 7.05 (1H, t, J=6.1 Hz), 9.09(2H, d, J=6.1 Hz).

B) 3′-bromo-2,4′-bipyridine

To a mixture of 1-(3-bromopyridin-4-yl)ethanone (1.0 g),1,3-dimethyl-2,3-dihydro-2-oxopyridinium sulfate (0.91 g) andacetonitrile (4.0 mL) was added triethylamine (1.1 mL) underice-cooling, and the mixture was warmed to 45° C. The mixture wasstirred at the same temperature for 1.5 hr, and concentrated underreduced pressure. To the residue were added acetic acid (4.0 mL) andammonium acetate (2.1 g), and the mixture was stirred at 120° C. for 4hr. The mixture was allowed to be cooled to room temperature, pouredinto 8M aqueous sodium hydroxide solution (35 mL, cooled to 0° C.), andthe mixture was extracted with ethyl acetate. The organic layer wasseparated, washed with water and saturated brine, and dried over sodiumsulfate, and the solvent was evaporated under reduced pressure. Theresidue was purified by silica gel column chromatography (NH, ethylacetate/hexane) to give the title compound (0.55 g).

¹H NMR (300 MHz, CDCl₃) δ 7.38 (1H, ddd, J=7.6, 4.9, 1.1 Hz), 7.52 (1H,dd, J=4.9, 0.8 Hz), 7.66-7.73 (1H, m), 7.78-7.87 (1H, m), 8.61 (1H, d,J=4.9 Hz), 8.73-8.79 (1H, m), 8.85 (1H, S).

C) ethyl 1-([2,4′-bipyridine]-3′-yl)piperidine-4-carboxylate

A mixture of 3′-bromo-2,4′-bipyridine (1.1 g),1,4-diazabicyclo[2.2.2]octane (0.25 g), ethyl isonipecotate (7.0 mL) andDIPEA (5.0 mL) was stirred with microwave irradiation at 200° C. for 18hr. The mixture was diluted with ethyl acetate/water, and extracted withethyl acetate. The organic layer was separated, washed with water andsaturated brine, and dried over sodium sulfate, and the solvent wasevaporated under reduced pressure. The residue was purified by silicagel column chromatography (NH, ethyl acetate/hexane) to give the titlecompound (0.44 g).

¹H NMR (300 MHz, CDCl₃) δ 1.25 (3H, t, J=7.2 Hz), 1.58-1.75 (1H, m),1.82-1.93 (2H, m), 2.28-2.40 (1H, m), 2.67-2.78 (2H, m), 3.12-3.22 (2H,m), 4.14 (2H, q, J=7.2 Hz), 7.25-7.31 (2H, m), 7.50 (1H, d, J=4.5 Hz),7.72-7.80 (1H, m), 8.08 (1H, d, J=8.3 Hz), 8.36-8.40 (2H, m), 8.71-8.76(1H, m).

D) 1-([2,4′-bipyridine]-3′-yl)piperidine-4-carboxylic acid

To a mixture of ethyl1-([2,4′-bipyridine]-3′-yl)piperidine-4-carboxylate (0.44 g) and THF(4.0 mL)/ethanol (1.0 mL) was added 2M aqueous sodium hydroxide solution(1.8 mL), and the mixture was stirred at 60° C. for 1.5 hr. The mixturewas neutralized with 2M hydrochloric acid (1.8 mL) under ice-cooling.The precipitate was collected by filtration, and washed with water togive the title compound (0.40 g).

¹H NMR (300 MHz, DMSO-d₆) δ 1.43-1.60 (2H, m), 1.71-1.82 (2H, m),2.21-2.35 (1H, m), 2.64-2.76 (2H, m), 2.99-3.10 (2H, m), 7.38-7.44 (1H,m), 7.47 (1H, d, J=4.9 Hz), 7.87-7.95 (1H, m), 8.08-8.14 (1H, m), 8.31(1H, d, J 4.9 Hz), 8.38 (1H, s), 8.70-8.74 (1H, m), 12.21 (1H, s).

E) (2R)-1-((1-(2,4′-bipyridine-3′-yl)piperidin-4-yl)carbonyl)pyrrolidine-2-carbonitrile

A mixture of 1-([2,4′-bipyridine]-3′-yl)piperidine-4-carboxylic acid (57mg), (R)-pyrrolidine-2-carbonitrile hydrochloride (32 mg), HATU (92 mg),DIPEA (0.11 mL) and DMF (2.0 mL) was stirred at room temperature for 16hr. The mixture was diluted with ethyl acetate/water, and extracted withethyl acetate. The organic layer was washed with water and saturatedbrine, and dried over sodium sulfate, and the solvent was evaporatedunder reduced pressure. The residue was purified by silica gel columnchromatography (NH, ethyl acetate/hexane and methanol/ethyl acetate) togive the title compound (52 mg).

¹H NMR (300 MHz, CDCl₃) δ 1.67-1.92 (4H, m), 2.09-2.45 (5H, m),2.66-2.79 (2H, m), 3.18-3.31 (2H, m), 3.45-3.56 (1H, m), 3.63-3.73 (1H,m), 4.61-4.78 (1H, m), 7.27-7.31 (1H, m), 7.52 (1H, d, J=4.9 Hz),7.75-7.83 (1H, m), 8.10 (1H, d, J=8.0 Hz), 8.37-8.41 (2H, m), 8.71-8.75(1H, m).

Example 144(2R,4S)-4-methoxy-1-((1-(4-(4-methyl-1H-pyrazol-1-yl)pyridin-3-yl)piperidin-4-yl)carbonyl)pyrrolidine-2-carbonitrileA) (2R,4S)-1-(tert-butoxycarbonyl)-4-hydroxypyrrolidine-2-carboxylicacid

A mixture of (2R,4S)-4-hydroxypyrrolidine-2-carboxylic acid (7.1 g),di-tert-butyl dicarbonate (25 mL), triethylamine (14 mL) and methanol(130 mL) was heated with reflux for 2 hr. The mixture was allowed to becooled to room temperature, and the solvent was evaporated under reducedpressure. To the residue was added sodium dihydrogenphosphate (590 mg)at 0° C., and the mixture was acidified (pH=2) with dilute hydrochloricacid. The mixture was stirred at 0° C. for 30 min, and extracted withethyl acetate/2-propanol (5:1). The organic layer was washed withsaturated brine, and dried over anhydrous magnesium sulfate, and thesolvent was evaporated under reduced pressure to give the title compound(11 g).

¹H NMR (300 MHz, CDCl₃) δ 1.40-1.52 (9H, m), 2.07-2.43 (2H, m),3.43-3.68 (2H, m), 4.34-4.57 (2H, m), 5.00 (2H, brs).

B) (2R,4S)-tert-butyl 2-carbamoyl-4-hydroxypyrrolidine-1-carboxylate

To a mixture of(2R,4S)-1-(tert-butoxycarbonyl)-4-hydroxypyrrolidine-2-carboxylic acid(11 g) and acetonitrile (130 mL) were added WSC hydrochloride (11 g) andHOBt monohydrate (8.7 g) at 0° C., and the mixture was stirred at roomtemperature for 2.5 hr. The mixture was cooled to 0° C., 28% aqueousammonia (25 mL) was added thereto, and the mixture was stirred at 0° C.for 15 min, and then overnight at room temperature. The insolublesubstance was removed by filtration, and the filtrate was concentratedunder reduced pressure. The residue was dissolved in ethylacetate-methanol (4:1), the insoluble substance was removed byfiltration, and the filtrate was concentrated under reduced pressure.The residue was purified by silica gel column chromatography(methanol/ethyl acetate) to give the title compound (7.0 g).

¹H NMR (300 MHz, DMSO-d₆) δ 1.31-1.41 (9H, m), 1.73-1.87 (1H, m),1.93-2.09 (1H, m), 3.20-3.28 (1H, m), 3.33-3.44 (1H, m), 4.02-4.13 (1H,m), 4.21 (1H, d, J=1.9 Hz), 4.96 (1H, d, J=3.4 Hz), 6.79-6.93 (1H, m),7.26-7.39 (1H, m).

C) (2R,4S)-tert-butyl 2-cyano-4-hydroxypyrrolidine-1-carboxylate

To a mixture of (2R,4S)-tert-butyl2-carbamoyl-4-hydroxypyrrolidine-1-carboxylate (3.0 g) and pyridine (30mL) was added trifluoroacetic anhydride (4.6 mL) at 0° C., and themixture was stirred at room temperature for 3 hr. To the mixture wereadded ethyl acetate and saturated aqueous sodium bicarbonate solution,and the mixture was extracted with ethyl acetate. The organic layer waswashed with water and saturated brine, and dried over anhydrous sodiumsulfate, and the solvent was evaporated under reduced pressure. Theresidue was purified by silica gel column chromatography (ethylacetate/hexane) to give the title compound (2.7 g).

¹H NMR (300 MHz, CD₃OD) δ 1.46-1.54 (9H, m), 2.29-2.40 (2H, m),3.37-3.56 (2H, m), 4.37-4.45 (1H, m), 4.61 (1H, t, J=8.0 Hz).

D) (2R,4S)-tert-butyl 2-cyano-4-methoxypyrrolidine-1-carboxylate

A mixture of (2R,4S)-tert-butyl2-cyano-4-hydroxypyrrolidine-1-carboxylate (550 mg), methyl iodide (3.2mL), silver oxide (1.0 g) and acetonitrile (6.0 mL) was heated withreflux for 5 hr under nitrogen atmosphere, and stirred at roomtemperature for 9 hr. The mixture was filtered through NH-silica gel andCelite pad, and the filtrate was concentrated under reduced pressure.The residue was purified by silica gel column chromatography (ethylacetate/hexane) to give the title compound (470 mg).

¹H NMR (300 MHz, DMSO-d₆) δ 1.43 (9H, s), 2.20-2.35 (1H, m), 2.37-2.47(1H, m), 3.31 (3H, s), 3.39-3.45 (2H, m), 3.98 (1H, brs), 4.55 (1H, t,J=7.8 Hz).

E) (2R,4S)-4-methoxypyrrolidine-2-carbonitrile

To a mixture of (2R,4S)-tert-butyl2-cyano-4-methoxypyrrolidine-1-carboxylate (85 mg) and acetonitrile (1.0mL) was added p-toluenesulfonic acid monohydrate (140 mg) at roomtemperature, and the mixture was stirred for 2 hr, and heated at 50° C.for 2 hr. The mixture was concentrated under reduced pressure, and theresidue was purified by MP-Carbonate (macroporous polystyrene anionexchange resin) to give the title compound (45 mg).

¹H NMR (300 MHz, CDCl₃) δ 2.09-2.36 (2H, m), 2.99-3.09 (1H, m),3.12-3.21 (1H, m), 3.29 (3H, s), 3.97-4.04 (1H, m), 4.10-4.21 (1H, m),5.25 (1H, brs).

F)(2R,4S)-4-methoxy-1-((1-(4-(4-methyl-1H-pyrazol-1-yl)pyridin-3-yl)piperidin-4-yl)carbonyl)pyrrolidine-2-carbonitrile

To a mixture of1-(4-(4-methyl-1H-pyrazol-1-yl)pyridin-3-yl)piperidine-4-carboxylic acid(52 mg) and DMF (1.0 mL) were added HATU (90 mg), triethylamine (0.051mL) and (2R,4S)-4-methoxypyrrolidine-2-carbonitrile (45 mg) at roomtemperature, and the mixture was stirred for 1.5 hr. To the mixture wasadded water, and the mixture was extracted with ethyl acetate. Theorganic layer was washed with water and saturated brine, and dried overanhydrous sodium sulfate, and the solvent was evaporated under reducedpressure. The residue was purified by silica gel column chromatography(NH, ethyl acetate/hexane) to give the title compound (32 mg).

¹H NMR (300 MHz, DMSO-d₆) δ 1.62-1.84 (4H, m), 2.13 (3H, s), 2.22-2.32(1H, m), 2.37-2.47 (1H, m), 2.67-2.83 (2H, m), 2.90-3.05 (2H, m), 3.25(3H, s), 3.34-3.40 (1H, m), 3.66-3.76 (2H, m), 4.05-4.11 (1H, m), 4.63(1H, t, J=8.0 Hz), 7.53 (1H, d, J=5.3 Hz), 7.63 (1H, s), 8.31 (1H, d,J=5.3 Hz), 8.41 (1H, s), 8.43 (1H, s).

Example 160 tert-butyl(1S,4S)-5-(4-phenylpyridin-3-yl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylateA) (1S,4S)-tert-butyl5-(4-chloropyridin-3-yl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate

A mixture of 3-bromo-4-chloropyridine (580 mg), (1S,4S)-tert-butyl2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (500 mg), Pd₂(dba)₃ (69mg), Xantphos (130 mg), sodium tert-butoxide (364 mg) and toluene (10mL) was stirred under argon atmosphere at 110° C. for 3 hr. The mixturewas filtered through Celite, and the filtrate was concentrated underreduced pressure. The residue was purified by silica gel columnchromatography (ethyl acetate/hexane), and then silica gel columnchromatography (NH, ethyl acetate/hexane) to give the title compound(590 mg).

¹H NMR (300 MHz, CDCl₃) δ 1.34-1.55 (9H, m), 1.86-2.03 (2H, m),3.24-3.51 (2H, m), 3.55-3.75 (1H, m), 3.92 (1H, dd, J=9.4, 2.3 Hz),4.44-4.66 (2H, m), 7.20 (1H, d, J=4.5 Hz), 7.95 (1H, d, J=5.3 Hz), 8.08(1H, s).

B) tert-butyl(1S,4S)-5-(4-phenylpyridin-3-yl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate

A mixture of (1S,4S)-tert-butyl5-(4-chloropyridin-3-yl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate(590 mg), phenylboronic acid (260 mg),tetrakis(triphenylphosphine)palladium(0) (110 mg) and potassiumcarbonate (790 mg) in DME/water (10/2.0 mL) was stirred with microwaveirradiation at 140° C. for 1 hr. The mixture was diluted with water, andthe mixture was extracted with ethyl acetate. The organic layer waswashed with saturated brine, dried over anhydrous sodium sulfate, andfiltered through NH silica gel (ethyl acetate), and the solvent wasevaporated under reduced pressure. The obtained solid was recrystallizedfrom ethyl acetate/hexane to give the title compound (440 mg).

¹H NMR (300 MHz, CDCl₃) δ 1.39 (9H, s), 1.72-1.89 (2H, m), 2.55 (1H, d,J=9.4 Hz), 2.87-3.04 (1H, m), 3.25-3.35 (1H, m), 3.51-3.61 (1H, m),4.17-4.40 (2H, m), 6.98-7.10 (1H, m), 7.29-7.46 (5H, m), 8.03-8.20 (2H,m).

Example 1612-cyclopropyl-1-((1S,4S)-5-(4-phenylpyridin-3-yl)-2,5-diazabicyclo[2.2.1]hept-2-yl)ethanone A)(1S,4S)-2-(4-phenylpyridin-3-yl)-2,5-diazabicyclo[2.2.1]heptanedihydrochloride

To a mixture of tert-butyl(1S,4S)-5-(4-phenylpyridin-3-yl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate(440 mg) and methanol (5.0 mL) was added 4M hydrogen chloride/ethylacetate solution (10 mL), and the mixture was stirred at roomtemperature for 2 hr. The mixture was concentrated under reducedpressure, to the residue were added methanol and toluene, and thesolvent was evaporated under reduced pressure to give the title compound(410 mg).

¹H NMR (300 MHz, DMSO-d₆) δ 1.85-2.10 (2H, m), 2.81-3.00 (2H, m),3.08-3.42 (2H, m), 4.22 (1H, brs), 4.63 (1H, s), 7.41-7.61 (5H, m), 7.72(1H, d, J=5.7 Hz), 8.34 (1H, d, J=5.7 Hz), 8.54 (1H, s), 9.14 (1H, brs),9.82 (1H, brs).

B)2-cyclopropyl-1-((1S,4S)-5-(4-phenylpyridin-3-yl)-2,5-diazabicyclo[2.2.1]hept-2-yl)ethanone

A mixture of(1S,4S)-2-(4-phenylpyridin-3-yl)-2,5-diazabicyclo[2.2.1]heptanedihydrochloride (140 mg), cyclopropylacetic acid (0.047 mL), HATU (190mg), triethylamine (0.29 mL) and DMF (3.0 mL) was stirred at roomtemperature for 3 hr. To the mixture was added water, and the mixturewas extracted with ethyl acetate. The organic layer was washed withsaturated brine, and dried over anhydrous sodium sulfate, and thesolvent was evaporated under reduced pressure. The residue was purifiedby silica gel column chromatography (NH, ethyl acetate/hexane), and theobtained solid was recrystallized from ethyl acetate/hexane to give thetitle compound (65 mg).

¹H NMR (300 MHz, CDCl₃) δ 0.02-0.15 (2H, m), 0.41-0.56 (2H, m),0.89-1.05 (1H, m), 1.74-2.26 (4H, m), 2.47-2.59 (1H, m), 2.97 (0.6H, dd,J=9.8, 2.3 Hz), 3.05 (0.4H, dd, J=9.4, 1.9 Hz), 3.37-3.47 (1H, m), 3.66(0.6H, d, J=9.4 Hz), 3.74 (0.4H, dd, J=11.5, 1.3 Hz), 4.22 (0.4H, s),4.36 (1H, brs), 4.75 (0.6H, s), 7.00-7.09 (1H, m), 7.30-7.46 (5H, m),8.06-8.21 (2H, m).

Example 165cyclopropyl(4-(5-fluoro-4-phenylpyridin-3-yl)piperazin-1-yl)methanone A)3-bromo-5-fluoro-4-phenylpyridine

To a mixture of 3-bromo-5-fluoropyridine (2.5 g), copper iodide (0.28g), lithium chloride (0.12 g) and THF (23 mL) was added dropwise phenylchloroformate (2.0 mL) at −20° C., and the mixture was stirred at thesame temperature for 30 min. To the mixture was added dropwise 2Mphenylmagnesium bromide THF solution (7.9 mL), and the mixture wasstirred at the same temperature for 1.5 hr. The mixture was stirredagain at room temperature for 30 min, saturated aqueous ammoniumchloride solution was added thereto, and the mixture was extracted withethyl acetate. The organic layer was separated, washed with water andsaturated brine, and dried over sodium sulfate, and the solvent wasevaporated under reduced pressure. A mixture of the obtained residue,2,3,5,6-tetrachlorocyclohexa-2,5-diene-1,4-dione (3.6 g) and toluene (15mL) was heated with reflux for 6 hr. The mixture was allowed to becooled to room temperature, diluted with 2M aqueous sodium hydroxidesolution (15 mL), stirred at room temperature for 10 min, and filteredthrough Celite (ethyl acetate). The organic layer of the filtrate wasseparated, washed with 2M aqueous sodium hydroxide solution and water,dried over sodium sulfate, and filtered through silica gel (NH, ethylacetate), and the filtrate was concentrated under reduced pressure. Theresidue was purified by silica gel column chromatography (NH, ethylacetate/hexane) to give the title compound (1.6 g).

¹H NMR (300 MHz, CDCl₃) δ 7.33-7.41 (2H, m), 7.46-7.56 (3H, m), 8.48(1H, s), 8.67 (1H, s).

B) tert-butyl 4-(5-fluoro-4-phenylpyridin-3-yl)piperazine-1-carboxylate

A mixture of 3-bromo-5-fluoro-4-phenylpyridine (600 mg), tert-butyl1-piperazine carboxylate (490 mg), Pd₂(dba)₃ (65 mg), Xantphos (83 mg),sodium tort-butoxide (270 mg) and toluene (10 mL) was stirred withmicrowave irradiation at 110° C. for 2 hr. The mixture was filteredthrough silica gel (NH, ethyl acetate), and the filtrate wasconcentrated under reduced pressure. The residue was purified by silicagel column chromatography (NH, ethyl acetate/hexane) to give the titlecompound (480 mg).

¹H NMR (300 MHz, CDCl₃) δ 1.43 (9H, s), 2.77-2.89 (4H, m), 3.22-3.33(4H, m), 7.37-7.57 (5H, m), 8.14 (1H, s), 8.27 (1H, s).

C) 1-(5-fluoro-4-phenylpyridin-3-yl)piperazine dihydrochloride

A mixture of tert-butyl4-(5-fluoro-4-phenylpyridin-3-yl)piperazine-1-carboxylate (480 mg) and2M hydrogen chloride/methanol solution (16 mL) was stirred at roomtemperature for 5 hr, and the solvent was evaporated under reducedpressure to give the title compound (440 mg).

¹H NMR (300 MHz, DMSO-d₆) δ 2.84-2.97 (4H, m), 3.02-3.13 (4H, m),7.45-7.64 (5H, m), 8.33 (1H, s), 8.47 (1H, d, J=0.8 Hz), 9.33 (2H, brs).

D) cyclopropyl(4-(5-fluoro-4-phenylpyridin-3-yl)piperazin-1-yl)methanone

To a mixture of 1-(5-fluoro-4-phenylpyridin-3-yl)piperazinedihydrochloride (100 mg) and THF (2.0 mL) were added successively DIPEA(0.21 mL) and cyclopropanecarbonyl chloride (0.036 mL) underice-cooling, and the mixture was stirred at room temperature for 2 hr.The mixture was diluted with ethyl acetate/saturated aqueous sodiumbicarbonate solution, and extracted with ethyl acetate. The organiclayer was separated, washed with water and saturated brine, dried oversodium sulfate, and filtered through silica gel (NH, ethyl acetate), andthe filtrate was concentrated under reduced pressure. The residue waspurified by silica gel column chromatography (ethyl acetate/hexane andmethanol/ethyl acetate) to give the title compound (92 mg).

¹H NMR (300 MHz, CDCl₃) δ 0.69-0.79 (2H, m), 0.90-1.01 (2H, m),1.58-1.71 (1H, m), 2.80-2.97 (4H, m), 3.44-3.59 (4H, m), 7.37-7.58 (5H,m), 8.15 (1H, s), 8.28 (1H, s).

Example 169 benzyl 4-(4-phenylpyrimidin-5-yl)piperazine-1-carboxylate A)benzyl 4-(2-oxo-2-phenylethyl)piperazine-1-carboxylate

To a mixture of benzyl piperazine-1-carboxylate (3.1 g), potassiumcarbonate (2.7 g) and acetonitrile (30 mL) was added dropwise a mixtureof 2-chloro-1-phenylethanone (2.0 g) and acetonitrile (20 mL) at roomtemperature, and the mixture was stirred overnight at room temperature.The solvent was evaporated under reduced pressure, the residue wasdiluted with water, and the mixture was extracted with ethyl acetate.The organic layer was washed with saturated brine, and dried overanhydrous magnesium sulfate, and the solvent was evaporated underreduced pressure. The residue was purified by silica gel columnchromatography (NH, ethyl acetate/hexane) to give the title compound(4.2 g).

MS (API+): [M+H]⁺ 339.1.

B) benzyl 4-(4-phenylpyrimidin-5-yl)piperazine-1-carboxylate

A mixture of benzyl 4-(2-oxo-2-phenylethyl)piperazine-1-carboxylate (4.2q) and N,N-dimethylformamide dimethyl acetal (40 mL) was stirredovernight at 100° C. The solvent was evaporated under reduced pressure.To a mixture of the residue, n-butanol (50 mL) and DIPEA (50 mL) wasadded formamidine acetate (7.7 g), and the mixture was stirred overnightat 110° C. The solvent was evaporated under reduced pressure, theresidue was diluted with water, and the mixture was extracted with ethylacetate. The organic layer was washed with water and saturated brine,and dried over anhydrous magnesium sulfate, and the solvent wasevaporated under reduced pressure. The residue was purified by purifiedby silica gel column chromatography (ethyl acetate/hexane), and thensilica gel column chromatography (NH, ethyl acetate/hexane) to give thetitle compound (3.1 g).

¹H NMR (300 MHz, CDCl₃) δ 2.92 (4H, brs), 3.46-3.59 (4H, m), 5.12 (2H,s), 7.29-7.39 (5H, m), 7.42-7.52 (3H, m), 7.99-8.07 (2H, m), 8.39 (1H,s), 8.95 (1H, s).

Example 175 N-benzyl-4-(4-phenylpyrimidin-5-yl)piperazine-1-carboxamideA) 4-phenyl-5-(piperazin-1-yl)pyrimidine

A mixture of benzyl 4-(4-phenylpyrimidin-5-yl)piperazine-1-carboxylate(3.1 g), 10% palladium carbon (about 50% water wet product, 0.30 g) andethanol (30 mL) was stirred at 50° C. for 3 hr under hydrogenatmosphere. The catalyst was removed by filtration, and the solvent wasevaporated under reduced pressure to give the title compound (1.9 g).

MS (API+): [M+H]⁺ 241.1.

B) N-benzyl-4-(4-phenylpyrimidin-5-yl)piperazine-1-carboxamide

To a mixture of 4-phenyl-5-(piperazin-1-yl)pyrimidine (100 mg) and THF(2.0 mL) was added benzyl isocyanate (0.054 mL) at room temperature, andthe mixture was stirred at room temperature for 4 hr. The solvent wasevaporated under reduced pressure. The residue was purified by silicagel column chromatography (NH, ethyl acetate/hexane), and the obtainedsolid was recrystallized from ethyl acetate/hexane to give the titlecompound (120 mg).

¹H NMR (300 MHz, CDCl₃) δ 2.85-3.00 (4H, m), 3.28-3.47 (4H, m), 4.42(2H, d, J=5.3 Hz), 4.69 (1H, t, J=5.1 Hz), 7.27-7.37 (5H, m), 7.41-7.51(3H, m), 7.99-8.07 (2H, m), 8.40 (1H, s), 8.95 (1H, s).

Example 186 methyl4-methyl-1-(4-phenylpyrimidin-5-yl)piperidine-4-carboxylate

A degassed mixture of 5-bromo-4-phenylpyrimidine (600 mg), methyl4-methylpiperidine-4-carboxylate hydrochloride (520 mg), Pd₂(dba)₃ (120mg), Xantphos (150 mg), sodium tert-butoxide (620 mg) and 1,4-dioxane(20 mL) was stirred with microwave irradiation at 110° C. for 9 hr. Themixture was filtered through silica gel (NH, ethyl acetate), and thefiltrate was concentrated under reduced pressure. The residue waspurified by silica gel column chromatography (NH, ethyl acetate/hexane)to give the title compound (130 mg).

¹H NMR (300 MHz, CDCl₃) δ 1.22 (3H, s), 1.41-1.54 (2H, m), 2.06-2.15(2H, m), 2.68-2.79 (2H, m), 2.98-3.08 (2H, m), 3.69 (3H, s), 7.39-7.51(3H, m), 8.01-8.07 (2H, m), 8.39 (1H, s), 8.89 (1H, s).

Example 198(2R)-1-((4-(4-(4-fluorophenyl)pyrimidin-5-yl)piperazin-1-yl)carbonyl)pyrrolidine-2-carbonitrileA) tert-butyl 4-(2-(4-fluorophenyl)-2-oxoethyl)piperazine-1-carboxylate

To a mixture of tert-butyl piperazine-1-carboxylate (5.9 g), potassiumcarbonate (6.0 g) and acetonitrile (60 mL) was added dropwise a mixtureof 2-chloro-1-(4-fluorophenyl)ethanone (5.0 g) and acetonitrile (40 mL)at room temperature, and the mixture was stirred overnight at roomtemperature. The solvent was evaporated under reduced pressure, theresidue was diluted with water, and the mixture was extracted with ethylacetate. The organic layer was washed with saturated brine, and driedover anhydrous magnesium sulfate, and the solvent was evaporated underreduced pressure to give the title compound (10 g).

MS (API+): [M+H]⁺ 323.2.

B) tert-butyl4-(4-(4-fluorophenyl)pyrimidin-5-yl)piperazine-1-carboxylate

A mixture of tert-butyl4-(2-(4-fluorophenyl)-2-oxoethyl)piperazine-1-carboxylate (8.2 g) andN,N-dimethylformamide dimethyl acetal (50 mL) was heated with reflux for5 hr. The solvent was evaporated under reduced pressure. To a mixture ofthe residue, n-butanol (40 mL) and DIPEA (40 mL) was added formamidineacetate (9.3 g), and the mixture was stirred overnight at 100° C. Thesolvent was evaporated under reduced pressure, the residue was dilutedwith water, and the mixture was extracted with ethyl acetate. Theorganic layer was washed with water and saturated brine, and dried overanhydrous magnesium sulfate, and the solvent was evaporated underreduced pressure. The residue was purified by silica gel columnchromatography (ethyl acetate/hexane) to give the title compound (5.81g).

MS (API+): [M+H]⁺ 359.2.

C) 4-(4-fluorophenyl)-5-(piperazin-1-yl)pyrimidine dihydrochloride

To a mixture of tert-butyl4-(4-(4-fluorophenyl)pyrimidin-5-yl)piperazine-1-carboxylate (5.8 g) andethyl acetate (50 mL) was added 4M hydrogen chloride/ethyl acetatesolution (50 mL) at room temperature, and the mixture was stirredovernight at room temperature. The mixture was diluted with ethylacetate, and the precipitate was collected by filtration to give thetitle compound (5.6 g).

MS (API+): [M+H]⁺ 259.1.

D)(2R)-1-((4-(4-(4-fluorophenyl)pyrimidin-5-yl)piperazin-1-yl)carbonyl)pyrrolidine-2-carbonitrile

To a mixture of 4-(4-fluorophenyl)-5-(piperazin-1-yl)pyrimidinedihydrochloride (200 mg), DIPEA (0.74 mL) and acetonitrile (2.0 mL) wasadded bis(trichloromethyl) carbonate (72 mg) at room temperature. Themixture was stirred at room temperature for 10 min, to the mixture wasadded (R)-pyrrolidine-2-carbonitrile hydrochloride (160 mg), and themixture was stirred overnight at room temperature. The mixture wasdiluted with water, and extracted with ethyl acetate. The organic layerwas washed with saturated brine, and dried over anhydrous magnesiumsulfate, and the solvent was evaporated under reduced pressure. Theresidue was purified by silica gel column chromatography (NH, ethylacetate/hexane and methanol/ethyl acetate) to give the title compound(58 mg).

¹H NMR (300 MHz, CDCl₃) δ 1.83-2.01 (1H, m), 2.01-2.39 (3H, m),2.87-3.05 (4H, m), 3.27-3.52 (6H, m), 4.73-4.85 (1H, m), 7.12-7.22 (2H,m), 8.07-8.16 (2H, m), 8.42 (1H, s), 8.95 (1H, s).

Example 219N-(4-fluorobenzyl)-4-(4-(4-methyl-1H-pyrazol-1-yl)pyridin-3-yl)piperazine-1-carboxamideA) tert-butyl4-(4-(4-methyl-1H-pyrazol-1-yl)pyridin-3-yl)piperazine-1-carboxylate

To a mixture of tert-butyl piperazine-1-carboxylate (0.41 g) and THF(5.0 mL) was added n-butyllithium hexane solution (1.6 M, 1.4 mL) at−78° C., and the mixture was stirred under nitrogen atmosphere for 30min. To the mixture was added a solution of3-fluoro-4-(4-methyl-1H-pyrazol-1-yl)pyridine (0.30 g) in THF (1.0 mL),and the mixture was stirred under nitrogen atmosphere at −78° C. for 15min. The mixture was allowed to be warmed to room temperature, andstirred for 1 hr. To the mixture was added saturated aqueous ammoniumchloride solution, and the mixture was extracted with ethyl acetate. Theorganic layer was washed with saturated brine, and dried over anhydrousmagnesium sulfate, and the solvent was evaporated under reducedpressure. The residue was purified by silica gel column chromatography(ethyl acetate/hexane) to give the title compound (0.26 g).

¹H NMR (300 MHz, CDCl₃) δ 1.46-1.49 (9H, m), 2.17 (3H, s), 2.81-2.88(4H, m), 3.45-3.56 (4H, m), 7.55 (1H, s), 7.58 (1H, d, J=5.3 Hz), 8.29(1H, s), 8.38 (2H, t, J=2.7 Hz).

B) 1-(4-(4-methyl-1H-pyrazol-1-yl)pyridin-3-yl)piperazine

To a mixture of tert-butyl4-(4-(4-methyl-1H-pyrazol-1-yl)pyridin-3-yl)piperazine-1-carboxylate(1.2 g), ethyl acetate (10 mL) and methanol (5.0 mL) was added 4Mhydrogen chloride/ethyl acetate solution (10 mL), and the mixture wasstirred overnight at room temperature. The solvent was evaporated underreduced pressure. To the residue was added water, and the mixture wasextracted with ethyl acetate. The aqueous solution was basified with 1Maqueous sodium hydroxide solution, saturated brine was added thereto,and the mixture was extracted with a mixed solvent of ethyl acetate andTHF. The organic layer was washed with saturated brine, and dried overanhydrous magnesium sulfate, and the solvent was evaporated underreduced pressure to give the title compound (0.86 g).

¹H NMR (300 MHz, CDCl₃) δ2.17 (3H, s), 2.81-2.90 (4H, m), 2.91-3.00 (4H,m), 7.54 (1H, s), 7.59 (1H, d, J=4.9 Hz), 8.32-8.43 (3H, m).

C)N-(4-fluorobenzyl)-4-(4-(4-methyl-1H-pyrazol-1-yl)pyridin-3-yl)piperazine-1-carboxamide

To a mixture of bis(trichloromethyl) carbonate (31 mg), DIPEA (0.11 mL)and THF (2.0 mL) was added a solution of (4-fluorophenyl)methanamine(0.035 mL) in THF (0.5 mL) under ice-cooling, and the mixture wasstirred for 10 min. To the mixture was added a solution of1-(4-(4-methyl-1H-pyrazol-1-yl)pyridin-3-yl)piperazine (50 mL) in THF(0.5 mL), and the mixture was stirred at room temperature for 30 min. Tothe mixture was added water, and the mixture was extracted with ethylacetate. The organic layer was washed with saturated brine, and driedover anhydrous magnesium sulfate, and the solvent was evaporated underreduced pressure. The residue was purified by silica gel columnchromatography (NH, ethyl acetate/hexane), and the obtained solid wascrystallized from ethyl acetate/hexane to give the title compound (51mg).

¹H NMR (300 MHz, CDCl₃) δ 2.16 (3H, s), 2.84-2.92 (4H, m), 3.41-3.51(4H, m), 4.40 (2H, d, J=5.7 Hz), 4.74 (1H, t, J=5.3 Hz), 6.97-7.06 (2H,m), 7.27-7.33 (2H, m), 7.53-7.59 (2H, m), 8.24 (1H, d, J=0.8 Hz),8.34-8.42 (2H, m).

Example 265(5-(methoxymethyl)-2,2-dimethylpyrrolidin-1-yl)(1-(4-(5-methyl-1,3,4-thiadiazol-2-yl)pyridin-3-yl)piperidin-4-yl)methanone(optical isomer)

Racemic(5-(methoxymethyl)-2,2-dimethylpyrrolidin-1-yl)(1-(4-(5-methyl-1,3,4-thiadiazol-2-yl)pyridin-3-yl)piperidin-4-yl)methanone(120 mg) was resolved by HPLC (column: CHIRALPAK AD, 50 mmID×500 mmL,mobile phase: hexane/ethanol/diethylamine=860/140/1) to give the titlecompound (56 mg) having a shorter retention time.

Example 266(5-(methoxymethyl)-2,2-dimethylpyrrolidin-1-yl)(1-(4-(5-methyl-1,3,4-thiadiazol-2-yl)pyridin-3-yl)piperidin-4-yl)methanone(optical isomer)

Racemic (5-(methoxymethyl)-2,2-dimethylpyrrolidin-1-yl)(1-(4-(5-methyl-1,3,4-thiadiazol-2-yl)pyridin-3-yl)piperidin-4-yl)methanone(120 mg) was resolved by HPLC (column: CHIRALPAK AD, 50 mmID×500 mmL,mobile phase: hexane/ethanol/diethylamine=860/140/1) to give the titlecompound (56 mg) having a longer retention time.

Example 2675,5-dimethyl-1-((1-(4-(5-methyl-1,3,4-thiadiazol-2-yl)pyridin-3-yl)piperidin-4-yl)carbonyl)prolinamide(optical isomer)

Racemic5,5-dimethyl-1-((1-(4-(5-methyl-1,3,4-thiadiazol-2-yl)pyridin-3-yl)piperidin-4-yl)carbonyl)prolinamide(63 mg) was resolved by HPLC (column: CHIRALPAK AS, 50 mmID×500 mmL,mobile phase: hexane/ethanol/diethylamine=700/300/1) to give the titlecompound (30 mg) having a shorter retention time.

Example 2685,5-dimethyl-1-((1-(4-(5-methyl-1,3,4-thiadiazol-2-yl)pyridin-3-yl)piperidin-4-yl)carbonyl)prolinamide(optical isomer)

Racemic5,5-dimethyl-1-((1-(4-(5-methyl-1,3,4-thiadiazol-2-yl)pyridin-3-yl)piperidin-4-yl)carbonyl)prolinamide(63 mg) was resolved by HPLC (column: CHIRALPAK AS, 50 mmID×500 mmL,mobile phase: hexane/ethanol/diethylamine=700/300/1) to give the titlecompound (22 mg) having a longer retention time.

Example 277N-cyclopropyl-1-(4-(4-fluorophenyl)pyrimidin-5-yl)-N-methylpiperidine-4-carboxamideA) ethyl 1-(2-(4-fluorophenyl)-2-oxoethyl)piperidine-4-carboxylate

To a mixture of ethyl piperidine-4-carboxylate (5.0 g), potassiumcarbonate (6.0 g) and acetonitrile (60 mL) was added dropwise a mixtureof 2-chloro-1-(4-fluorophenyl)ethanone (5.0 g) and acetonitrile (40 mL)at room temperature, and the mixture was stirred overnight at roomtemperature. The solvent was evaporated under reduced pressure, theresidue was diluted with water, and the mixture was extracted with ethylacetate. The organic layer was washed with saturated brine, and driedover anhydrous magnesium sulfate, and the solvent was evaporated underreduced pressure to give the title compound (8.7 g).

¹H NMR (300 MHz, CDCl₃) δ 1.19-1.30 (3H, m), 1.75-1.98 (4H, m),2.15-2.37 (3H, m), 2.92 (2H, dt, J=11.6, 3.5 Hz), 3.72 (2H, s), 4.13(2H, q, J=7.2 Hz), 7.05-7.17 (2H, m), 8.01-8.13 (2H, m).

B) ethyl 1-(4-(4-fluorophenyl)pyrimidin-5-yl)piperidine-4-carboxylate

A mixture of ethyl1-(2-(4-fluorophenyl)-2-oxoethyl)piperidine-4-carboxylate (8.0 g) andN,N-dimethylformamide dimethyl acetal (50 mL) was heated with reflux for5 hr, and the solvent was evaporated under reduced pressure. To amixture of the obtained residue, n-butanol (40 mL) and DIPEA (40 mL) wasadded formamidine acetate (9.9 g), and the mixture was stirred overnightat 100° C. To the mixture was added 1M hydrochloric acid, and thesolvent was evaporated under reduced pressure. The residue was dilutedwith water, and the mixture was extracted with ethyl acetate. Theorganic layer was washed with water and saturated brine, and dried overanhydrous magnesium sulfate, and the solvent was evaporated underreduced pressure. The residue was purified by silica gel columnchromatography (ethyl acetate/hexane), and the obtained solid wascrystallized from ethyl acetate/hexane to give the title compound (4.7g).

¹H NMR (300 MHz, CDCl₃) δ 1.27 (3H, t, J=7.2 Hz), 1.67-1.84 (2H, m),1.87-2.00 (2H, m), 2.38 (1H, tt, J=11.2, 4.0 Hz), 2.68 (2H, td, J=11.5,2.7 Hz), 3.21 (2H, dt, J=12.2, 3.2 Hz), 4.16 (2H, q, J=7.2 Hz),7.12-7.21 (2H, m), 8.07-8.18 (2H, m), 8.41 (1H, s), 8.90 (1H, s).

C) 1-(4-(4-fluorophenyl)pyrimidin-5-yl)piperidine-4-carboxylic acid

Ethyl 1-(4-(4-fluorophenyl)pyrimidin-5-yl)piperidine-4-carboxylate (2.2g) was dissolved in THF (20 mL) and methanol (5.0 mL), to the mixturewas added 2M aqueous sodium hydroxide solution (6.6 mL), and the mixturewas stirred at room temperature for 3.5 hr. The mixture wasconcentrated, the residue was neutralized with 2M hydrochloric acid, andthe precipitated solid was collected by filtration to give the titlecompound (2.0 g).

¹H NMR (300 MHz, DMSO-d₆) δ 1.51-1.68 (2H, m), 1.76-1.88 (2H, m),2.24-2.38 (1H, m), 2.62-2.75 (2H, m), 3.06-3.18 (2H, m), 7.30-7.41 (2H,m), 8.09-8.20 (2H, m), 8.54 (1H, s), 8.85 (1H, s), 12.25 (1H, brs).

D)N-cyclopropyl-1-(4-(4-fluorophenyl)pyrimidin-5-yl)-N-methylpiperidine-4-carboxamide

A mixture of 1-(4-(4-fluorophenyl)pyrimidin-5-yl)piperidine-4-carboxylicacid (0.10 g), N-methylcyclopropanamine (28 mg), HATU (0.15 g), DIPEA(0.15 mL) and DMF (2.0 mL) was stirred at room temperature for 4 hr. Tothe mixture was added water, and the mixture was extracted with ethylacetate. The organic layer was washed with water and saturated brine,and dried over anhydrous sodium sulfate, and the solvent was evaporatedunder reduced pressure. The residue was purified by silica gel columnchromatography (NH, ethyl acetate/hexane), and the obtained solid wascrystallized from ethyl acetate/heptane to give the title compound (94mg).

¹H NMR (300 MHz, CDCl₃) δ 0.70-0.81 (2H, m), 0.85-0.96 (2H, m),1.65-1.77 (2H, m), 1.82-1.99 (2H, m), 2.62-2.75 (3H, m), 2.93 (3H, s),3.02-3.17 (1H, m), 3.24-3.37 (2H, m), 7.13-7.22 (2H, m), 8.11-8.20 (2H,m), 8.42 (1H, s), 8.90 (1H, s).

Example 278(3-fluoroazetidin-1-yl)(1-(4-(4-fluorophenyl)pyrimidin-5-yl)piperidin-4-yl)methanone

A mixture of 1-(4-(4-fluorophenyl)pyrimidin-5-yl)piperidine-4-carboxylicacid (0.10 g), 3-fluoroazetidine hydrochloride (0.056 g), HATU (0.16 g),DIPEA (0.23 mL) and DMF (2.0 mL) was stirred at room temperature for 18hr. The mixture was diluted with ethyl acetate and water, and extractedwith ethyl acetate. The organic layer was washed with water andsaturated brine, and dried over anhydrous sodium sulfate, and thesolvent was evaporated under reduced pressure. The residue was purifiedby silica gel column chromatography (NH, ethyl acetate/hexane), andtriturated with diethyl ether to give the title compound (0.11 g).

¹H NMR (300 MHz, CDCl₃) δ1.62-1.94 (4H, m), 2.18-2.31 (1H, m), 2.59-2.73(2H, m), 3.21-3.34 (2H, m), 4.03-4.49 (4H, m), 5.18-5.46 (1H, m),7.12-7.21 (2H, m), 8.09-8.17 (2H, m), 8.41 (1H, s), 8.90 (1H, s).

Example 280(3-fluoroazetidin-1-yl)(1-(4-(4-methyl-1H-pyrazol-1-yl)pyridin-3-yl)piperidin-4-yl)methanone

A mixture of1-(4-(4-methyl-1H-pyrazol-1-yl)pyridin-3-yl)piperidine-4-carboxylic acid(60 mg), 3-fluoroazetidine hydrochloride (28 mg), HATU (96 mg), DIPEA(0.091 mL) and DMF (2.0 mL) was stirred at room temperature for 4 hr. Tothe mixture was added water, and the mixture was extracted with ethylacetate. The organic layer was washed with water and saturated brine,and dried over anhydrous sodium sulfate, and the solvent was evaporatedunder reduced pressure. The residue was purified by silica gel columnchromatography (NH, ethyl acetate/hexane), and the obtained solid wascrystallized from ethyl acetate/heptane to give the title compound (68mg).

¹H NMR (300 MHz, CDCl₃) δ 1.67-1.99 (4H, m), 2.17 (3H, s), 2.20-2.33(1H, m), 2.64-2.78 (2H, m), 3.07-3.19 (2H, m), 4.04-4.52 (4H, m),5.19-5.48 (1H, m), 7.54 (1H, s), 7.60 (1H, d, J=5.3 Hz), 8.32-8.36 (2H,m), 8.39 (1H, s).

Example 281(1-(4-(4-chloro-1H-pyrazol-1-yl)pyridin-3-yl)piperidin-4-yl)(3-fluoroazetidin-1-yl)methanone

A mixture of1-(4-(4-chloro-1H-pyrazol-1-yl)pyridin-3-yl)piperidine-4-carboxylic acid(0.060 g), 3-fluoroazetidine hydrochloride (0.026 g), HATU (0.089 g),DIPEA (0.085 mL) and DMF (2.0 mL) was stirred at room temperature for 4hr. The mixture was diluted with ethyl acetate and water, and extractedwith ethyl acetate. The organic layer was washed with water andsaturated brine, and dried over anhydrous sodium sulfate, and thesolvent was evaporated under reduced pressure. The residue was purifiedby silica gel column chromatography (NH, ethyl acetate/hexane), andcrystallized from ethyl acetate/heptane to give the title compound(0.062 g).

¹H NMR (300 MHz, CDCl₃) δ 1.69-2.01 (4H, m), 2.21-2.36 (1H, m),2.68-2.81 (2H, m), 3.05-3.18 (2H, m), 4.03-4.53 (4H, m), 5.19-5.48 (1H,m), 7.59 (1H, d, J=5.3 Hz), 7.66 (1H, s), 8.39 (1H, d, J=5.3 Hz), 8.44(1H, s), 8.56 (1H, s).

Example 282((3S)-3-fluoropyrrolidin-1-yl)(1-(4-(4-methyl-1H-pyrazol-1-yl)pyridin-3-yl)piperidin-4-yl)methanone

A mixture of1-(4-(4-methyl-1H-pyrazol-1-yl)pyridin-3-yl)piperidine-4-carboxylic acid(60 mg), (S)-3-fluoropyrrolidine hydrochloride (32 mg), HATU (96 mg),DIPEA (0.091 mL) and DMF (2.0 mL) was stirred at room temperature for 4hr. To the mixture was added water, and the mixture was extracted withethyl acetate. The organic layer was washed with water and saturatedbrine, and dried over anhydrous sodium sulfate, and the solvent wasevaporated under reduced pressure. The residue was purified by silicagel column chromatography (NH, ethyl acetate/hexane), and the obtainedsolid was crystallized from ethyl acetate/heptane to give the titlecompound (68 mg).

¹H NMR (300 MHz, CDCl₃) δ1.68-2.10 (5H, m), 2.17 (3H, s), 2.20-2.56 (2H,m), 2.66-2.79 (2H, m), 3.09-3.20 (2H, m), 3.45-3.99 (4H, m), 5.14-5.44(1H, m), 7.54 (1H, s), 7.61 (1H, d, J=5.3 Hz), 8.32-8.37 (2H, m), 8.40(1H, s).

Example 283((3R)-3-fluoropyrrolidin-1-yl)(1-(4-(4-methyl-1H-pyrazol-1-yl)pyridin-3-yl)piperidin-4-yl)methanone

A mixture of1-(4-(4-methyl-1H-pyrazol-1-yl)pyridin-3-yl)piperidine-4-carboxylic acid(60 mg), (R)-3-fluoropyrrolidine hydrochloride (32 mg), HATU (96 mg),DIPEA (0.091 mL) and DMF (2.0 mL) was stirred at room temperature for 4hr. To the mixture was added water, and the mixture was extracted withethyl acetate. The organic layer was washed with water and saturatedbrine, and dried over anhydrous sodium sulfate, and the solvent wasevaporated under reduced pressure. The residue was purified by silicagel column chromatography (NH, ethyl acetate/hexane), and the obtainedsolid was crystallized from ethyl acetate/heptane to give the titlecompound (64 mg).

¹H NMR (300 MHz, CDCl₃) δ1.70-2.15 (5H, m), 2.17 (3H, s), 2.21-2.56 (2H,m), 2.65-2.80 (2H, m), 3.08-3.20 (2H, m), 3.45-4.00 (4H, m), 5.15-5.43(1H, m), 7.54 (1H, s), 7.61 (1H, d, J=5.3 Hz), 8.33-8.37 (2H, m), 8.40(1H, s).

Example 284(1-(4-(4-chloro-1H-pyrazol-1-yl)pyridin-3-yl)piperidin-4-yl)((3S)-3-fluoropyrrolidin-1-yl)methanone

A mixture of1-(4-(4-chloro-1H-pyrazol-1-yl)pyridin-3-yl)piperidine-4-carboxylic acid(0.060 g), (S)-3-fluoropyrrolidine hydrochloride (0.030 g), HATU (0.089g), DIPEA (0.085 mL) and DMF (2.0 mL) was stirred at room temperaturefor 4 hr. The mixture was diluted with ethyl acetate and water, andextracted with ethyl acetate. The organic layer was washed with waterand saturated brine, and dried over anhydrous sodium sulfate, and thesolvent was evaporated under reduced pressure. The residue was purifiedby silica gel column chromatography (NH, ethyl acetate/hexane), andcrystallized from ethyl acetate/heptane to give the title compound(0.064 g).

¹H NMR (300 MHz, CDCl₃) δ 1.72-2.58 (7H, m), 2.69-2.84 (2H, m),3.08-3.20 (2H, m), 3.46-4.01 (4H, m), 5.13-5.44 (1H, m), 7.60 (1H, d,J=5.3 Hz), 7.66 (1H, s), 8.39 (1H, d, J=5.3 Hz), 8.45 (1H, s), 8.59 (1H,s).

Example 285(1-(4-(4-chloro-1H-pyrazol-1-yl)pyridin-3-yl)piperidin-4-yl)((3R)-3-fluoropyrrolidin-1-yl)methanone

A mixture of1-(4-(4-chloro-1H-pyrazol-1-yl)pyridin-3-yl)piperidine-4-carboxylic acid(60 mg), (R)-3-fluoropyrrolidine hydrochloride (30 mg), HATU (89 mg),DIPEA (0.085 mL) and DMF (2.0 mL) was stirred at room temperature for 2hr. To the mixture was added water, and the mixture was extracted withethyl acetate. The organic layer was washed with water and saturatedbrine, and dried over anhydrous sodium sulfate, and the solvent wasevaporated under reduced pressure. The residue was purified by silicagel column chromatography (NH, ethyl acetate/hexane), and the obtainedsolid was crystallized from ethyl acetate/heptane to give the titlecompound (63 mg).

¹H NMR (300 MHz, CDCl₃) δ 1.74-2.59 (7H, m), 2.69-2.84 (2H, m),3.07-3.20 (2H, m), 3.45-3.99 (4H, m), 5.15-5.44 (1H, m), 7.60 (1H, d,J=5.3 Hz), 7.66 (1H, s), 8.39 (1H, d, J=5.3 Hz), 8.46 (1H, s), 8.59 (1H,s).

Example 286(1-(4-(4-fluorophenyl)pyrimidin-5-yl)piperidin-4-yl)((3S)-3-fluoropyrrolidin-1-yl)methanone

A mixture of 1-(4-(4-fluorophenyl)pyrimidin-5-yl)piperidine-4-carboxylicacid (0.060 g), (S)-3-fluoropyrrolidine hydrochloride (0.030 g), HATU(0.091 g), DIPEA (0.087 mL) and DMF (2.0 mL) was stirred at roomtemperature for 4 hr. The mixture was diluted with ethyl acetate andwater, and extracted with ethyl acetate. The organic layer was washedwith water and saturated brine, and dried over anhydrous sodium sulfate,and the solvent was evaporated under reduced pressure. The residue waspurified by silica gel column chromatography (NH, ethyl acetate/hexane),and crystallized from ethyl acetate/heptane to give the title compound(0.059 g).

¹H NMR (300 MHz, CDCl₃) δ1.66-2.54 (7H, m), 2.61-2.74 (2H, m), 3.25-3.36(2H, m), 3.45-3.98 (4H, m), 5.14-5.41 (1H, m), 7.12-7.22 (2H, m),8.11-8.18 (2H, m), 8.42 (1H, s), 8.90 (1H, s).

Example 28(1-(4-(4-fluorophenyl)pyrimidin-5-yl)piperidin-4-yl)((3R)-3-fluoropyrrolidin-1-yl)methanone

A mixture of 1-(4-(4-fluorophenyl)pyrimidin-5-yl)piperidine-4-carboxylicacid (60 mg), (R)-3-fluoropyrrolidine hydrochloride (30 mg), HATU (91mg), DIPEA (0.087 mL) and DMF (2.0 mL) was stirred at room temperaturefor 4 hr. To the mixture was added water, and the mixture was extractedwith ethyl acetate. The organic layer was washed with water andsaturated brine, and dried over anhydrous sodium sulfate, and thesolvent was evaporated under reduced pressure. The residue was purifiedby silica gel column chromatography (NH, ethyl acetate/hexane), and theobtained solid was crystallized from ethyl acetate/heptane to give thetitle compound (60 mg).

¹H NMR (300 MHz, CDCl₃) δ 1.64-2.53 (7H, m), 2.61-2.75 (2H, m),3.24-3.37 (2H, m), 3.46-3.98 (4H, m), 5.13-5.43 (1H, m), 7.12-7.21 (2H,m), 8.10-8.18 (2H, m), 8.42 (1H, s), 8.90 (1H, s).

Example 2881-(4-(4-fluorophenyl)pyrimidin-5-yl)-N-methyl-N-(tetrahydro-2H-pyran-4-yl)piperidine-4-carboxamide

A mixture of 1-(4-(4-fluorophenyl)pyrimidin-5-yl)piperidine-4-carboxylicacid (60 mg), N-methyl-N-(tetrahydro-2H-pyran-4-yl)amine (28 mg), HATU(91 mg), DIPEA (0.087 mL) and DMF (2.0 mL) was stirred at roomtemperature for 4 hr. To the mixture was added water, and the mixturewas extracted with ethyl acetate. The organic layer was washed withwater and saturated brine, and dried over anhydrous sodium sulfate, andthe solvent was evaporated under reduced pressure. The residue waspurified by silica gel column chromatography (NH, ethyl acetate/hexane),and the obtained solid was crystallized from ethyl acetate/heptane togive the title compound (68 mg).

¹H NMR (300 MHz, CDCl₃) δ 1.46-2.06 (8H, m), 2.48-2.77 (3H, m),2.81-2.95 (3H, m), 3.21-3.57 (4H, m), 3.96-4.13 (2H, m), 4.62-4.84 (1H,m), 7.12-7.21 (2H, m), 8.10-8.19 (2H, m), 8.42 (1H, s), 8.90 (1H, s).

Example 2901-(4-(4-fluorophenyl)pyrimidin-5-yl)-N-((3S)-tetrahydrofuran-3-yl)piperidine-4-carboxamide

A mixture of 1-(4-(4-fluorophenyl)pyrimidin-5-yl)piperidine-4-carboxylicacid (0.30 g), (S)-tetrahydrofuran-3-amine hydrochloride (0.15 g), HATU(0.45 g), DIPEA (0.43 mL) and DMF (5.0 mL) was stirred at roomtemperature for 4 hr. To the mixture was added water, and the mixturewas extracted with ethyl acetate. The organic layer was washed withwater and saturated brine, and dried over anhydrous sodium sulfate, andthe solvent was evaporated under reduced pressure. The residue waspurified by silica gel column chromatography (NH, ethyl acetate/hexane),and the obtained solid was crystallized from ethyl acetate/heptane togive the title compound (0.32 g).

¹H NMR (300 MHz, CDCl₃) δ 1.70-1.87 (5H, m), 2.06-2.19 (1H, m),2.22-2.36 (1H, m), 2.59-2.71 (2H, m), 3.21-3.34 (2H, m), 3.66 (1H, dd,J=9.4, 2.3 Hz), 3.74-3.85 (2H, m), 3.89-3.99 (1H, m), 4.47-4.60 (1H, m),5.63 (1H, d, J=6.4 Hz), 7.12-7.21 (2H, m), 8.08-8.16 (2H, m), 8.41 (1H,s), 8.90 (1H, s).

Example 2911-(4-(4-fluorophenyl)pyrimidin-5-yl)-N-((3R)-tetrahydrofuran-3-yl)piperidine-4-carboxamide

A mixture of 1-(4-(4-fluorophenyl)pyrimidin-5-yl)piperidine-4-carboxylicacid (0.30 g), (R)-tetrahydrofuran-3-amine hydrochloride (0.15 g), HATU(0.45 g), DIPEA (0.43 mL) and DMF (5.0 mL) was stirred at roomtemperature for 4 hr. To the mixture was added water, and the mixturewas extracted with ethyl acetate. The organic layer was washed withwater and saturated brine, and dried over anhydrous sodium sulfate, andthe solvent was evaporated under reduced pressure. The residue waspurified by silica gel column chromatography (NH, ethyl acetate/hexane),and the obtained solid was crystallized from ethyl acetate/heptane togive the title compound (0.34 g).

¹H NMR (300 MHz, CDCl₃) δ1.71-1.86 (5H, m), 2.04-2.18 (1H, m), 2.22-2.36(1H, m), 2.59-2.71 (2H, m), 3.22-3.32 (2H, m), 3.62-3.69 (1H, m),3.74-3.85 (2H, m), 3.89-3.99 (1H, m), 4.47-4.60 (1H, m), 5.63 (1H, d,J=7.5 Hz), 7.12-7.22 (2H, m), 8.06-8.17 (2H, m), 8.41 (1H, s), 8.90 (1H,s).

Example 2921-(4-(4-methyl-1H-pyrazol-1-yl)pyridin-3-yl)-N-((3S)-tetrahydrofuran-3-yl)piperidine-4-carboxamide

A mixture of1-(4-(4-methyl-1H-pyrazol-1-yl)pyridin-3-yl)piperidine-4-carboxylic acid(1.0 g), (S)-tetrahydrofuran-3-amine hydrochloride (0.43 g), HATU (1.7g), triethylamine (1.9 mL) and DMF (12 mL) was stirred at roomtemperature for 3 hr. To the mixture was added water, and the mixturewas extracted with ethyl acetate. The organic layer was washed withwater and saturated brine, and dried over anhydrous magnesium sulfate,and the solvent was evaporated under reduced pressure. The residue waspurified by silica gel column chromatography (NH, ethyl acetate/hexane),and the obtained solid was crystallized from ethyl acetate/hexane togive the title compound (0.82 g).

¹H NMR (300 MHz, CDCl₃) δ 1.72-1.92 (5H, m), 2.07-2.21 (4H, m),2.22-2.38 (1H, m), 2.69 (2H, dt, J=11.7, 7.2 Hz), 3.12 (2H, d, J=12.1Hz), 3.66 (1H, dd, J=9.5, 2.7 Hz), 3.74-3.87 (2H, m), 3.88-4.01 (1H, m),4.47-4.61 (1H, m), 5.73 (1H, d, J=7.2 Hz), 7.54 (1H, s), 7.60 (1H, d,J=5.3 Hz), 8.31 (1H, d, J=0.8 Hz), 8.35 (1H, d, J=5.3 Hz), 8.39 (1H, s).

Example 2931-(4-(4-chloro-1H-pyrazol-1-yl)pyridin-3-yl)-N-((3S)-tetrahydrofuran-3-yl)piperidine-4-carboxamide

A mixture of1-(4-(4-chloro-1H-pyrazol-1-yl)pyridin-3-yl)piperidine-4-carboxylic acid(0.50 g), (S)-tetrahydrofuran-3-amine hydrochloride (0.20 g), HATU (0.81g), triethylamine (0.91 mL) and DMF (5.4 mL) was stirred at roomtemperature for 3 hr. To the mixture was added water, and the mixturewas extracted with ethyl acetate. The organic layer was washed withwater and saturated brine, and dried over anhydrous magnesium sulfate,and the solvent was evaporated under reduced pressure. The residue waspurified by silica gel column chromatography (NH, ethyl acetate/hexane),and the obtained solid was crystallized from ethyl acetate/hexane togive the title compound (0.51 g).

¹H NMR (300 MHz, CDCl₃) δ1.72-1.96 (5H, m), 2.10-2.37 (2H, m), 2.73 (2H,td, J=10.8, 4.2 Hz), 3.04-3.18 (2H, m), 3.67 (1H, dd, J=9.5, 2.3 Hz),3.74-3.87 (2H, m), 3.89-4.00 (1H, m), 4.49-4.62 (1H, m), 5.71 (1H, d,J=7.2 Hz), 7.59 (1H, d, J=5.3 Hz), 7.66 (1H, d, J=0.8 Hz), 8.39 (1H, d,J=5.3 Hz), 8.44 (1H, s), 8.54 (1H, d, J=0.8 Hz).

Example 2941-(4-(4-methyl-1H-pyrazol-1-yl)pyridin-3-yl)-N-((3R)-tetrahydrofuran-3-yl)piperidine-4-carboxamide

A mixture of1-(4-(4-methyl-1H-pyrazol-1-yl)pyridin-3-yl)piperidine-4-carboxylic acid(1.0 g), (R)-tetrahydrofuran-3-amine hydrochloride (0.43 g), HATU (1.7g), triethylamine (1.9 mL) and DMF (12 mL) was stirred at roomtemperature for 3 hr. To the mixture was added water, and the mixturewas extracted with ethyl acetate. The organic layer was washed withwater and saturated brine, and dried over anhydrous magnesium sulfate,and the solvent was evaporated under reduced pressure. The residue waspurified by silica gel column chromatography (NH, ethyl acetate/hexane),and the obtained solid was crystallized from ethyl acetate/hexane togive the title compound (0.83 g).

¹H NMR (300 MHz, CDCl₃) δ1.67-1.93 (5H, m), 2.05-2.37 (5H, m), 2.69 (2H,dt, J=12.0, 7.2 Hz), 3.12 (2H, d, J=11.7 Hz), 3.67 (1H, dd, J=9.5, 2.3Hz), 3.73-3.87 (2H, m), 3.88-4.00 (1H, m), 4.55 (1H, dtd, J=7.6, 4.8,2.8 Hz), 5.75 (1H, d, J=7.2 Hz), 7.54 (1H, s), 7.60 (1H, d, J=4.9 Hz),8.31 (1H, s), 8.34 (1H, d, J=5.3 Hz), 8.39 (1H, s).

Example 2951-(4-(4-chloro-1H-pyrazol-1-yl)pyridin-3-yl)-N-((3R)-tetrahydrofuran-3-yl)piperidine-4-carboxamide

A mixture of1-(4-(4-chloro-1H-pyrazol-1-yl)pyridin-3-yl)piperidine-4-carboxylic acid(0.50 g), (R)-tetrahydrofuran-3-amine hydrochloride (0.20 g), HATU (0.81g), triethylamine (0.91 mL) and DMF (5.4 mL) was stirred at roomtemperature for 3 hr. To the mixture was added water, and the mixturewas extracted with ethyl acetate. The organic layer was washed withwater and saturated brine, and dried over anhydrous magnesium sulfate,and the solvent was evaporated under reduced pressure. The residue waspurified by silica gel column chromatography (NH, ethyl acetate/hexane),and the obtained solid was crystallized from ethyl acetate/hexane togive the title compound (0.50 g).

¹H NMR (300 MHz, CDCl₃) δ1.69-1.97 (5H, m), 2.10-2.37 (2H, m), 2.73 (2H,td, J=10.8, 4.2 Hz), 3.05-3.17 (2H, m), 3.67 (1H, dd, J=9.5, 2.3 Hz),3.73-3.87 (2H, m), 3.89-4.01 (1H, m), 4.55 (1H, ddt, J=7.6, 5.1, 2.4Hz), 5.69 (1H, d, J=7.2 Hz), 7.59 (1H, d, J=5.3 Hz), 7.66 (1H, s), 8.39(1H, d, J=5.3 Hz), 8.44 (1H, s), 8.54 (1H, d, J=0.8 Hz).

Example 296N-methyl-1-(4-(4-methyl-1H-pyrazol-1-yl)pyridin-3-yl)-N-(tetrahydro-2H-pyran-4-yl)piperidine-4-carboxamide

A mixture of1-(4-(4-methyl-1H-pyrazol-1-yl)pyridin-3-yl)piperidine-4-carboxylic acid(80 mg), N-methyl-N-(tetrahydro-2H-pyran-4-yl)amine (39 mg), HATU (0.13g), DIPEA (0.12 mL) and DMF (2.0 mL) was stirred at room temperature for4 hr. To the mixture was added water, and the mixture was extracted withethyl acetate. The organic layer was washed with water and saturatedbrine, and dried over anhydrous sodium sulfate, and the solvent wasevaporated under reduced pressure. The residue was purified by silicagel column chromatography (NH, ethyl acetate/hexane), and the obtainedsolid was crystallized from ethyl acetate/heptane to give the titlecompound (73 mg).

¹H NMR (300 MHz, CDCl₃) δ 1.49-2.07 (8H, m), 2.17 (3H, s), 2.52-2.81(3H, m), 2.84-2.96 (3H, m), 3.08-3.21 (2H, m), 3.38-3.57 (2H, m),3.97-4.13 (2H, m), 4.67-4.83 (1H, m), 7.54 (1H, s), 7.61 (1H, d, J=5.3Hz), 8.33-8.39 (2H, m), 8.40 (1H, s).

Example 297N-(4-fluorobenzyl)-N-methyl-4-(4-(4-methyl-1H-pyrazol-1-yl)pyridin-3-yl)piperazine-1-carboxamide

To a mixture ofN-(4-fluorobenzyl)-4-(4-(4-methyl-1H-pyrazol-1-yl)pyridin-3-yl)piperazine-1-carboxamide(0.20 g) and DMF (3.0 mL) was added sodium hydride (60%, 30 mg) underice-cooling, and the mixture was stirred at the same temperature for 30min. To the mixture was added methyl iodide (0.047 mL) underice-cooling, and the mixture was stirred at the same temperature for 30min. To the mixture were added saturated aqueous ammonium chloridesolution, ethyl acetate and pyridine, and the mixture was extracted withethyl acetate. The organic layer was washed with water and saturatedbrine, and dried over anhydrous sodium sulfate, and the solvent wasevaporated under reduced pressure. The residue was purified by silicagel column chromatography (NH, ethyl acetate/hexane) to give the titlecompound (0.18 g).

¹H NMR (300 MHz, CDCl₃) δ2.17 (3H, s), 2.78 (3H, s), 2.88-2.95 (4H, m),3.30-3.38 (4H, m), 4.38 (2H, s), 6.97-7.07 (2H, m), 7.19-7.26 (2H, m),7.55 (1H, s), 7.58 (1H, d, J=5.3 Hz), 8.30 (1H, s), 8.35-8.41 (2H, m).

Example 298N-benzyl-N-methyl-4-(4-phenylpyrimidin-5-yl)piperazine-1-carboxamide

To a mixture ofN-benzyl-4-(4-phenylpyrimidin-5-yl)piperazine-1-carboxamide (0.15 g) andDMF (3.0 mL) was added sodium hydride (60%, 24 mg) under ice-cooling,and the mixture was stirred at the same temperature for 30 min. To themixture was added methyl iodide (0.038 mL), and the mixture was stirredfor 1.5 hr under ice-cooling. To the mixture were added saturatedaqueous ammonium chloride solution, ethyl acetate and pyridine, and themixture was extracted with ethyl acetate. The organic layer was washedwith water and saturated brine, and dried over anhydrous sodium sulfate,and the solvent was evaporated under reduced pressure. The residue waspurified by silica gel column chromatography (NH, ethyl acetate/hexane),and crystallized from ethyl acetate/heptane to give the title compound(0.11 g).

¹H NMR (300 MHz, CDCl₃) δ2.75 (3H, s), 2.93-3.02 (4H, m), 3.25-3.33 (4H,m), 4.40 (2H, s), 7.19-7.37 (5H, m), 7.42-7.52 (3H, m), 8.03-8.11 (2H,m), 8.41 (1H, s), 8.94 (1H, s).

Example 299(1-(4-(4-chloro-1H-pyrazol-1-yl)pyridin-3-yl)piperidin-4-yl)((3S)-3-methoxypyrrolidin-1-yl)methanone

A mixture of1-(4-(4-chloro-1H-pyrazol-1-yl)pyridin-3-yl)piperidine-4-carboxylic acid(0.10 g), (S)-3-methoxypyrrolidine hydrochloride (49 mg), HATU (0.16 g),triethylamine (0.18 mL) and DMF (1.1 mL) was stirred at room temperaturefor 3 hr. To the mixture was added water, and the mixture was extractedwith ethyl acetate. The organic layer was washed with water andsaturated brine, and dried over anhydrous magnesium sulfate, and thesolvent was evaporated under reduced pressure. The residue was purifiedby silica gel column chromatography (NH, ethyl acetate/hexane), and theobtained solid was crystallized from ethyl acetate/hexane to give thetitle compound (0.066 g).

¹H NMR (300 MHz, CDCl₃) δ 1.73-2.22 (6H, m), 2.37-2.55 (1H, m),2.69-2.82 (2H, m), 3.06-3.20 (2H, m), 3.34 (3H, d, J=5.3 Hz), 3.41-3.76(4H, m), 3.92-4.07 (1H, m), 7.60 (1H, d, J=5.3 Hz), 7.66 (1H, s), 8.38(1H, d, J=5.3 Hz), 8.45 (1H, s), 8.60 (1H, s).

Example 300(1-(4-(4-chloro-1H-pyrazol-1-yl)pyridin-3-yl)piperidin-4-yl)((3R)-3-methoxypyrrolidin-1-yl)methanone

A mixture of1-(4-(4-chloro-1H-pyrazol-1-yl)pyridin-3-yl)piperidine-4-carboxylic acid(0.10 g), (R)-3-methoxypyrrolidine hydrochloride (49 mg), HATU (0.16 g),triethylamine (0.18 mL) and DMF (1.1 mL) was stirred at room temperaturefor 3 hr. To the mixture was added water, and the mixture was extractedwith ethyl acetate. The organic layer was washed with water andsaturated brine, and dried over anhydrous magnesium sulfate, and thesolvent was evaporated under reduced pressure. The residue was purifiedby silica gel column chromatography (NH, ethyl acetate/hexane), and theobtained solid was crystallized from ethyl acetate/hexane to give thetitle compound (0.076 g).

¹H NMR (300 MHz, CDCl₃) δ 1.73-2.20 (6H, m), 2.36-2.55 (1H, m),2.68-2.83 (2H, m), 3.13 (2H, dd, J=11.4, 3.0 Hz), 3.34 (3H, d, J=5.3Hz), 3.41-3.76 (4H, m), 3.92-4.07 (1H, m), 7.60 (1H, d, J=5.3 Hz), 7.66(1H, s), 8.39 (1H, d, J=5.3 Hz), 8.45 (1H, s), 8.60 (1H, s).

Example 301((3S)-3-methoxypyrrolidin-1-yl)(1-(4-(4-methyl-1H-pyrazol-1-yl)pyridin-3-yl)piperidin-4-yl)methanone

A mixture of1-(4-(4-methyl-1H-pyrazol-1-yl)pyridin-3-yl)piperidine-4-carboxylic acid(0.10 g), (S)-3-methoxypyrrolidine hydrochloride (53 mg), HATU (0.17 g),triethylamine (0.20 mL) and DMF (1.2 mL) was stirred at room temperaturefor 3 hr. To the mixture was added water, and the mixture was extractedwith ethyl acetate. The organic layer was washed with water andsaturated brine, and dried over anhydrous magnesium sulfate, and thesolvent was evaporated under reduced pressure. The residue was purifiedby silica gel column chromatography (NH, ethyl acetate/hexane) to givethe title compound (0.050 g).

¹H NMR (300 MHz, CDCl₃) δ 1.71-2.20 (9H, m), 2.44 (1H, d, J=17.0 Hz),2.72 (2H, td, J=11.9, 2.7 Hz), 3.14 (2H, d, J=12.1 Hz), 3.34 (3H, d,J=5.3 Hz), 3.42-3.77 (4H, m), 3.92-4.06 (1H, m), 7.53 (1H, s), 7.61 (1H,d, J=5.3 Hz), 8.31-8.42 (3H, m).

Example 302((3R)-3-methoxypyrrolidin-1-yl)(1-(4-(4-methyl-1H-pyrazol-1-yl)pyridin-3-yl)piperidin-4-yl)methanone

A mixture of1-(4-(4-methyl-1H-pyrazol-1-yl)pyridin-3-yl)piperidine-4-carboxylic acid(100 mg), (R)-3-methoxypyrrolidine hydrochloride (53 mg), HATU (0.17 g),triethylamine (0.20 mL) and DMF (1.2 mL) was stirred at room temperaturefor 3 hr. To the mixture was added water, and the mixture was extractedwith ethyl acetate. The organic layer was washed with water andsaturated brine, and dried over anhydrous magnesium sulfate, and thesolvent was evaporated under reduced pressure. The residue was purifiedby silica gel column chromatography (NH, ethyl acetate/hexane) to givethe title compound (0.039 g).

¹H NMR (300 MHz, CDCl₃) δ 1.72-2.21 (9H, m), 2.33-2.55 (1H, m), 2.72(2H, td, J=12.0, 2.5 Hz), 3.14 (2H, d, J=12.1 Hz), 3.34 (3H, d, J=5.3Hz), 3.43-3.76 (4H, m), 3.90-4.11 (1H, m), 7.53 (1H, s), 7.61 (1H, d,J=4.9 Hz), 8.29-8.43 (3H, m).

Example 303(1-(4-(4-fluorophenyl)pyrimidin-5-yl)piperidin-4-yl)((3S)-3-methoxypyrrolidin-1-yl)methanone

A mixture of 1-(4-(4-fluorophenyl)pyrimidin-5-yl)piperidine-4-carboxylicacid (0.10 g), (S)-3-methoxypyrrolidine hydrochloride (50 mg), HATU(0.16 g), triethylamine (0.19 mL) and DMF (1.1 mL) was stirred at roomtemperature for 3 hr. To the mixture was added water, and the mixturewas extracted with ethyl acetate. The organic layer was washed withwater and saturated brine, and dried over anhydrous magnesium sulfate,and the solvent was evaporated under reduced pressure. The residue waspurified by silica gel column chromatography (NH, ethyl acetate/hexane)to give the title compound (0.073 g).

¹H NMR (300 MHz, CDCl₃) δ 1.65-2.20 (6H, m), 2.34-2.51 (1H, m), 2.67(2H, td, J=11.8, 2.5 Hz), 3.21-3.37 (5H, m), 3.41-3.74 (4H, m),3.89-4.05 (1H, m), 7.09-7.23 (2H, m), 8.07-8.19 (2H, m), 8.41 (1H, s),8.90 (1H, s).

Example 304(1-(4-(4-fluorophenyl)pyrimidin-5-yl)piperidin-4-yl)((3R)-3-methoxypyrrolidin-1-yl)methanone

A mixture of 1-(4-(4-fluorophenyl)pyrimidin-5-yl)piperidine-4-carboxylicacid (0.10 g), (R)-3-methoxypyrrolidine hydrochloride (50 mg), HATU(0.16 g), triethylamine (0.19 mL) and DMF (1.1 mL) was stirred at roomtemperature for 3 hr. To the mixture was added water, and the mixturewas extracted with ethyl acetate. The organic layer was washed withwater and saturated brine, and dried over anhydrous magnesium sulfate,and the solvent was evaporated under reduced pressure. The residue waspurified by silica gel column chromatography (NH, ethyl acetate/hexane)to give the title compound (0.074 g).

¹H NMR (300 MHz, CDCl₃) δ 1.66-2.22 (6H, m), 2.31-2.51 (1H, m),2.58-2.76 (2H, m), 3.21-3.38 (5H, m), 3.39-3.77 (4H, m), 3.90-4.07 (1H,m), 7.16 (2H, t, J=8.7 Hz), 8.15 (2H, dd, J=8.7, 5.7 Hz), 8.41 (1H, s),8.90 (1H, s).

Example 305N-methyl-1-(4-(4-methyl-1H-pyrazol-1-yl)pyridin-3-yl)-N-((3S)-tetrahydrofuran-3-yl)piperidine-4-carboxamide

To a mixture of1-(4-(4-methyl-1H-pyrazol-1-yl)pyridin-3-yl)-N-((3S)-tetrahydrofuran-3-yl)piperidine-4-carboxamide(0.12 g) and DMF (2.0 mL) was added sodium hydride (60%, 20 mg) underice-cooling, and the mixture was stirred for 30 min. To the mixture wasadded methyl iodide (0.032 mL), and the mixture was stirred for 1 hrunder ice-cooling. To the mixture were added saturated aqueous ammoniumchloride solution, ethyl acetate and pyridine, and the mixture wasextracted with ethyl acetate. The organic layer was washed with waterand saturated brine, and dried over anhydrous sodium sulfate, and thesolvent was evaporated under reduced pressure. The residue was purifiedby silica gel column chromatography (NH, ethyl acetate/hexane), andcrystallized from ethyl acetate/heptane to give the title compound(0.084 g).

¹H NMR (300 MHz, CDCl₃) δ1.69-2.05 (5H, m), 2.17 (3H, s), 2.20-2.35 (1H,m), 2.51-3.03 (6H, m), 3.08-3.20 (2H, m), 3.60-3.85 (3H, m), 4.00-4.13(1H, m), 5.30-5.43 (1H, m), 7.54 (1H, s), 7.61 (1H, d, J=5.3 Hz),8.33-8.37 (2H, m), 8.40 (1H, s).

Example 306N-methyl-1-(4-(4-methyl-1H-pyrazol-1-yl)pyridin-3-yl)-N-((3R)-tetrahydrofuran-3-yl)piperidine-4-carboxamide

To a mixture of1-(4-(4-methyl-1H-pyrazol-1-yl)pyridin-3-yl)-N-((3R)-tetrahydrofuran-3-yl)piperidine-4-carboxamide(0.12 g) and DMF (2.0 mL) was added sodium hydride (60%, 20 mg) underice-cooling, and the mixture was stirred for 30 min. To the mixture wasadded methyl iodide (0.032 mL), and the mixture was stirred for 1 hrunder ice-cooling. To the mixture were added saturated aqueous ammoniumchloride solution, ethyl acetate and pyridine, and the mixture wasextracted with ethyl acetate. The organic layer was washed with waterand saturated brine, and dried over anhydrous sodium sulfate, and thesolvent was evaporated under reduced pressure. The residue was purifiedby silica gel column chromatography (NH, ethyl acetate/hexane), andcrystallized from ethyl acetate/heptane to give the title compound(0.066 g).

¹H NMR (300 MHz, CDCl₃) δ1.70-2.03 (5H, m), 2.17 (3H, s), 2.20-2.35 (1H,m), 2.51-3.03 (6H, m), 3.09-3.19 (2H, m), 3.61-3.85 (3H, m), 4.01-4.14(1H, m), 5.30-5.43 (1H, m), 7.54 (1H, s), 7.61 (1H, d, J=5.3 Hz),8.33-8.37 (2H, m), 8.40 (1H, s).

Example 3071-(4-(4-chloro-1H-pyrazol-1-yl)pyridin-3-yl)-N-methyl-N-((3S)-tetrahydrofuran-3-yl)piperidine-4-carboxamide

To a mixture of1-(4-(4-chloro-1H-pyrazol-1-yl)pyridin-3-yl)-N-((3S)-tetrahydrofuran-3-yl)piperidine-4-carboxamide(0.12 g) and DMF (2.0 mL) was added sodium hydride (60%, 19 mg) underice-cooling, and the mixture was stirred for 30 min. To the mixture wasadded methyl iodide (0.030 mL), and the mixture was stirred for 1 hrunder ice-cooling. To the mixture were added saturated aqueous ammoniumchloride solution, ethyl acetate and pyridine, and the mixture wasextracted with ethyl acetate. The organic layer was washed with waterand saturated brine, and dried over anhydrous sodium sulfate, and thesolvent was evaporated under reduced pressure. The residue was purifiedby silica gel column chromatography (NH, ethyl acetate/hexane) to givethe title compound (0.094 g).

¹H NMR (300 MHz, CDCl₃) δ1.71-2.03 (5H, m), 2.19-2.35 (1H, m), 2.53-3.02(6H, m), 3.07-3.19 (2H, m), 3.60-3.85 (3H, m), 4.01-4.12 (1H, m),5.30-5.44 (1H, m), 7.60 (1H, d, J=5.3 Hz), 7.66 (1H, s), 8.39 (1H, d,J=4.9 Hz), 8.45 (1H, s), 8.58 (1H, s).

Example 3081-(4-(4-chloro-1H-pyrazol-1-yl)pyridin-3-yl)-N-methyl-N-((3R)-tetrahydrofuran-3-yl)piperidine-4-carboxamide

To a mixture of1-(4-(4-chloro-1H-pyrazol-1-yl)pyridin-3-yl)-N-((3R)-tetrahydrofuran-3-yl)piperidine-4-carboxamide(0.12 g) and DMF (2.0 mL) was added sodium hydride (60%, 19 mg) underice-cooling, and the mixture was stirred for 30 min. To the mixture wasadded methyl iodide (0.030 mL), and the mixture was stirred for 1 hrunder ice-cooling. To the mixture were added saturated aqueous ammoniumchloride solution, ethyl acetate and pyridine, and the mixture wasextracted with ethyl acetate. The organic layer was washed with waterand saturated brine, and dried over anhydrous sodium sulfate, and thesolvent was evaporated under reduced pressure. The residue was purifiedby silica gel column chromatography (NH, ethyl acetate/hexane) to givethe title compound (0.092 g).

¹H NMR (300 MHz, CDCl₃) δ1.70-2.03 (5H, m), 2.18-2.35 (1H, m), 2.53-3.04(6H, m), 3.08-3.20 (2H, m), 3.60-3.85 (3H, m), 4.01-4.12 (1H, m),5.31-5.43 (1H, m), 7.60 (1H, d, J=5.3 Hz), 7.66 (1H, s), 8.39 (1H, d,J=5.3 Hz), 8.45 (1H, s), 8.58 (1H, s).

Example 3091-(4-(4-fluorophenyl)pyrimidin-5-yl)-N-methyl-N-((3S)-tetrahydrofuran-3-yl)piperidine-4-carboxamide

To a mixture of1-(4-(4-fluorophenyl)pyrimidin-5-yl)-N-((3S)-tetrahydrofuran-3-yl)piperidine-4-carboxamide(0.12 g) and DMF (2.0 mL) was added sodium hydride (60%, 19 mg) underice-cooling, and the mixture was stirred for 30 min. To the mixture wasadded methyl iodide (0.034 mL), and the mixture was stirred for 2.5 hrunder ice-cooling. To the mixture were added saturated aqueous ammoniumchloride solution, ethyl acetate and pyridine, and the mixture wasextracted with ethyl acetate. The organic layer was washed with waterand saturated brine, and dried over anhydrous sodium sulfate, and thesolvent was evaporated under reduced pressure. The residue was purifiedby silica gel column chromatography (NH, ethyl acetate/hexane), andcrystallized from ethyl acetate/heptane to give the title compound(0.091 g).

¹H NMR (300 MHz, CDCl₃) δ1.66-2.03 (5H, m), 2.17-2.35 (1H, m), 2.46-2.75(3H, m), 2.83-3.01 (3H, m), 3.23-3.35 (2H, m), 3.60-3.82 (3H, m),4.00-4.12 (1H, m), 5.27-5.42 (1H, m), 7.12-7.22 (2H, m), 8.09-8.19 (2H,m), 8.42 (1H, s), 8.90 (1H, s).

Example 3101-(4-(4-fluorophenyl)pyrimidin-5-yl)-N-methyl-N-((3R)-tetrahydrofuran-3-yl)piperidine-4-carboxamide

To a mixture of1-(4-(4-fluorophenyl)pyrimidin-5-yl)-N-((3R)-tetrahydrofuran-3-yl)piperidine-4-carboxamide(0.12 g) and DMF (2.0 mL) was added sodium hydride (60%, 19 mg) underice-cooling, and the mixture was stirred for 30 min. To the mixture wasadded methyl iodide (0.034 mL), and the mixture was stirred for 2.5 hrunder ice-cooling. To the mixture were added saturated aqueous ammoniumchloride solution, ethyl acetate and pyridine, and the mixture wasextracted with ethyl acetate. The organic layer was washed with waterand saturated brine, and dried over anhydrous sodium sulfate, and thesolvent was evaporated under reduced pressure. The residue was purifiedby silica gel column chromatography (NH, ethyl acetate/hexane), andcrystallized from ethyl acetate/heptane to give the title compound(0.087 g).

¹H NMR (300 MHz, CDCl₃) δ1.65-2.02 (5H, m), 2.16-2.36 (1H, m), 2.48-2.77(3H, m), 2.84-3.02 (3H, m), 3.24-3.35 (2H, m), 3.60-3.81 (3H, m),4.00-4.11 (1H, m), 5.29-5.41 (1H, m), 7.12-7.21 (2H, m), 8.10-8.19 (2H,m), 8.42 (1H, s), 8.90 (1H, s).

Example 311N-(2-fluoroethyl)-1-(4-(4-methyl-1H-pyrazol-1-yl)pyridin-3-yl)-N-(tetrahydro-2H-pyran-4-yl)piperidine-4-carboxamide

To a mixture of1-(4-(4-methyl-1H-pyrazol-1-yl)pyridin-3-yl)-N-(tetrahydro-2H-pyran-4-yl)piperidine-4-carboxamide(0.12 g) and DMF (2.0 mL) was added sodium hydride (60%, 19 mg), and themixture was stirred for 30 min. To the mixture was added a solution of2-fluoroethyl 4-methylbenzenesulfonate (0.11 g) in DMF (1.0 mL), and themixture was stirred at room temperature for 16 hr. To the mixture wasadded saturated aqueous ammonium chloride solution, and the mixture wasextracted with ethyl acetate. The organic layer was washed with waterand saturated brine, and dried over anhydrous sodium sulfate, and thesolvent was evaporated under reduced pressure. The residue was purifiedby silica gel column chromatography (ethyl acetate/hexane) to give thetitle compound (3.4 mg).

¹H NMR (300 MHz, CDCl₃) δ 1.61-2.04 (8H, m), 2.17 (3H, s), 2.56-2.85(3H, m), 3.06-3.22 (2H, m), 3.38-3.89 (5H, m), 3.97-4.15 (2H, m),4.35-4.74 (2H, m), 7.54 (1H, s), 7.61 (1H, d, J=5.3 Hz), 8.31-8.45 (3H,m).

Example 312N-(2-fluoroethyl)-1-(4-(4-methyl-1H-pyrazol-1-yl)pyridin-3-yl)-N-((3S)-tetrahydrofuran-3-yl)piperidine-4-carboxamide

To a mixture of1-(4-(4-methyl-1H-pyrazol-1-yl)pyridin-3-yl)-N-((3S)-tetrahydrofuran-3-yl)piperidine-4-carboxamide(0.12 g) and DMF (2.0 mL) was added sodium hydride (60%, 20 mg), and themixture was stirred for 30 min. To the mixture was added a solution of2-fluoroethyl 4-methylbenzenesulfonate (0.11 g) in DMF (1.0 mL), and themixture was stirred at room temperature for 16 hr. To the mixture wasadded saturated aqueous ammonium chloride solution, and the mixture wasextracted with ethyl acetate. The organic layer was washed with waterand saturated brine, and dried over anhydrous sodium sulfate, and thesolvent was evaporated under reduced pressure. The residue was purifiedby silica gel column chromatography (ethyl acetate/hexane) to give thetitle compound (12 mg).

¹H NMR (300 MHz, CDCl₃) δ 1.70-2.06 (5H, m), 2.18 (3H, s), 2.23-2.41(1H, m), 2.62-2.84 (3H, m), 3.06-3.22 (2H, m), 3.51-3.90 (5H, m),4.03-4.14 (1H, m), 4.42-5.00 (3H, m), 7.54 (1H, s), 7.61 (1H, d, J=5.3Hz), 8.31-8.43 (3H, m).

Example 313N-(2-fluoroethyl)-1-(4-(4-methyl-1H-pyrazol-1-yl)pyridin-3-yl)-N-((3R)-tetrahydrofuran-3-yl)piperidine-4-carboxamide

To a mixture of1-(4-(4-methyl-1H-pyrazol-1-yl)pyridin-3-yl)-N-((3R)-tetrahydrofuran-3-yl)piperidine-4-carboxamide(0.12 g) and DMF (2.0 mL) was added sodium hydride (60%, 20 mg), and themixture was stirred for 30 min. To the mixture was added a solution of2-fluoroethyl 4-methylbenzenesulfonate (0.11 g) in DMF (1.0 mL), and themixture was stirred at room temperature for 16 hr. To the mixture wasadded saturated aqueous ammonium chloride solution, and the mixture wasextracted with ethyl acetate. The organic layer was washed with waterand saturated brine, and dried over anhydrous sodium sulfate, and thesolvent was evaporated under reduced pressure. The residue was purifiedby silica gel column chromatography (ethyl acetate/hexane) to give thetitle compound (12 mg).

¹H NMR (300 MHz, CDCl₃) δ 1.70-2.04 (5H, m), 2.17 (3H, s), 2.22-2.39(1H, m), 2.62-2.84 (3H, m), 3.07-3.22 (2H, m), 3.50-3.92 (5H, m),4.03-4.14 (1H, m), 4.43-5.01 (3H, m), 7.54 (1H, s), 7.61 (1H, d, J=5.3Hz), 8.31-8.44 (3H, m).

Example 314N-benzyl-N-(2-fluoroethyl)-4-(4-phenylpyrimidin-5-yl)piperazine-1-carboxamide

To a mixture ofN-benzyl-4-(4-phenylpyrimidin-5-yl)piperazine-1-carboxamide (0.11 g),15-crown 5-ether (0.078 mL) and THF (2.0 mL) was added sodium hydride(16 mg) under ice-cooling, and the mixture was stirred at roomtemperature for 30 min. To the mixture was added a solution (1.0 mL) of2-fluoroethyl 4-methylbenzenesulfonate (0.12 g) in THF, and the mixturewas stirred at room temperature for 4 days. The reaction was quenchedwith aqueous ammonium chloride solution, and the mixture was extractedwith ethyl acetate. The organic layer was washed with water andsaturated brine, and dried over anhydrous sodium sulfate, and thesolvent was evaporated under reduced pressure. The residue was purifiedby silica gel column chromatography (NH, ethyl acetate/hexane andmethanol/ethyl acetate) to give the title compound (43 mg).

¹H NMR (300 MHz, CDCl₃) δ 2.91-3.01 (4H, m), 3.28-3.50 (6H, m),4.42-4.65 (4H, m), 7.17-7.38 (5H, m), 7.43-7.52 (3H, m), 8.03-8.10 (2H,m), 8.40 (1H, s), 8.94 (1H, s).

Example 315N-(4-fluorobenzyl)-N-(2-fluoroethyl)-4-(4-(4-methyl-1H-pyrazol-1-yl)pyridin-3-yl)piperazine-1-carboxamide

To a mixture ofN-(4-fluorobenzyl)-4-(4-(4-methyl-1H-pyrazol-1-yl)pyridin-3-yl)piperazine-1-carboxamide(0.12 g), 15-crown 5-ether (0.079 mL) and THF (2.0 mL) was added sodiumhydride (0.016 g) at 0° C., and the mixture was stirred at roomtemperature for 30 min. To the mixture was added a solution (1.0 mL) of2-fluoroethyl 4-methylbenzenesulfonate (0.12 g) in THF, and the mixturewas stirred at room temperature for 4 days. To the mixture was addedaqueous ammonium chloride solution, and the mixture was extracted withethyl acetate. The organic layer was washed with water and saturatedbrine, and dried over anhydrous sodium sulfate, and the solvent wasevaporated under reduced pressure. The residue was purified by silicagel column chromatography (NH, ethyl acetate/hexane and methanol/ethylacetate) to give the title compound (0.072 g).

¹H NMR (300 MHz, CDCl₃) δ 2.17 (3H, s), 2.87-2.96 (4H, m), 3.32-3.50(6H, m), 4.44-4.67 (4H, m), 6.99-7.09 (2H, m), 7.17-7.25 (7H, m), 7.55(1H, s), 7.58 (1H, d, J=4.9 Hz), 8.28 (1H, s), 8.36-8.40 (2H, m).

Example 316((3S)-3-fluoropyrrolidin-1-yl)(1-(4-(5-methyl-1,3-thiazol-2-yl)pyridin-3-yl)piperidin-4-yl)methanone

A mixture of1-(4-(5-methyl-1,3-thiazol-2-yl)pyridin-3-yl)piperidine-4-carboxylicacid (0.080 g), (S)-3-fluoropyrrolidine hydrochloride (0.040 g), HATU(0.12 g), DIPEA (0.12 mL) and DMF (2.0 mL) was stirred at roomtemperature for 18 hr. The mixture was diluted with ethyl acetate andwater, and extracted with ethyl acetate. The organic layer was washedwith water and saturated brine, and dried over anhydrous sodium sulfate,and the solvent was evaporated under reduced pressure. The residue waspurified by silica gel column chromatography (NH, ethyl acetate/hexane),and crystallized from ethyl acetate/heptane to give the title compound(0.075 g).

¹H NMR (300 MHz, CDCl₃) δ 1.78-2.65 (10H, m), 2.87-3.02 (2H, m),3.17-3.28 (2H, m), 3.49-4.03 (4H, m), 5.16-5.47 (1H, m), 7.60 (1H, d,J=0.9 Hz), 8.09 (1H, d, J=5.1 Hz), 8.45 (1H, d, J=5.1 Hz), 8.59 (1H, s).

Example 317(3-fluoroazetidin-1-yl)(1-(4-(5-methyl-1,3-thiazol-2-yl)pyridin-3-yl)piperidin-4-yl)methanone

A mixture of1-(4-(5-methyl-1,3-thiazol-2-yl)pyridin-3-yl)piperidine-4-carboxylicacid (0.080 g), 3-fluoroazetidine hydrochloride (0.035 g), HATU (0.12g), DIPEA (0.12 mL) and DMF (2.0 mL) was stirred at room temperature for18 hr. The mixture was diluted with ethyl acetate and water, andextracted with ethyl acetate. The organic layer was washed with waterand saturated brine, and dried over anhydrous sodium sulfate, and thesolvent was evaporated under reduced pressure. The residue was purifiedby silica gel column chromatography (NH, ethyl acetate/hexane), andcrystallized from ethyl acetate/heptane to give the title compound(0.071 g).

¹H NMR (300 MHz, CDCl₃) δ 1.74-1.92 (2H, m), 2.12-2.28 (2H, m),2.29-2.41 (1H, m), 2.53 (3H, d, J=0.9 Hz), 2.86-2.99 (2H, m), 3.15-3.27(2H, m), 4.07-4.57 (4H, m), 5.22-5.50 (1H, m), 7.60 (1H, d, J=0.9 Hz),8.09 (1H, d, J=5.1 Hz), 8.45 (1H, d, J=5.1 Hz), 8.58 (1H, s).

Example 318(1-(4-(4-bromo-1H-pyrazol-1-yl)pyridin-3-yl)piperidin-4-yl)((3S)-3-fluoropyrrolidin-1-yl)methanoneA) ethyl1-(4-(4-bromo-1H-pyrazol-1-yl)pyridin-3-yl)piperidine-4-carboxylate

A mixture of 4-(4-bromo-1H-pyrazol-1-yl)-3-fluoropyridine (3.0 g), ethylpiperidine-4-carboxylate (4.2 mL) and NMP (12 mL) was stirred at 180° C.for 4 hr. The mixture was purified by silica gel column chromatography(ethyl acetate/hexane), and washed with ethyl acetate/hexane to give thetitle compound (2.3 g).

¹H NMR (300 MHz, CDCl₃) δ 1.28 (3H, t, J=7.1 Hz), 1.73-1.91 (2H, m),1.95-2.07 (2H, m), 2.35-2.50 (1H, m), 2.68-2.82 (2H, m), 2.99-3.13 (2H,m), 4.18 (2H, q, J=7.2 Hz), 7.58 (1H, d, J=5.1 Hz), 7.70 (1H, s), 8.39(1H, d, J=5.1 Hz), 8.44 (1H, s), 8.58 (1H, s).

B) 1-(4-(4-bromo-1H-pyrazol-1-yl)pyridin-3-yl)piperidine-4-carboxylicacid

A mixture of ethyl1-(4-(4-bromo-1H-pyrazol-1-yl)pyridin-3-yl)piperidine-4-carboxylate (1.2g), 2M aqueous sodium hydroxide solution (2.4 mL), THF (4.0 mL) andethanol (4.0 mL) was stirred at room temperature for 3 hr. The mixturewas concentrated, and the residue was neutralized with 2M hydrochloricacid (2.4 mL). The precipitate was collected by filtration, washed withwater, and dried under reduced pressure to give the title compound (1.1g).

¹H NMR (300 MHz, DMSO-d₆) δ 1.54-1.72 (2H, m), 1.77-1.90 (2H, m),2.26-2.41 (1H, m), 2.64-2.77 (2H, m), 2.83-2.95 (2H, m), 7.52 (1H, d,J=5.1 Hz), 7.96 (1H, s), 8.36 (1H, d, J=5.1 Hz), 8.48 (1H, s), 8.77 (1H,s), 12.26 (1H, s).

C)(1-(4-(4-bromo-1H-pyrazol-1-yl)pyridin-3-yl)piperidin-4-yl)((3S)-3-fluoropyrrolidin-1-yl)methanone

A mixture of1-(4-(4-bromo-1H-pyrazol-1-yl)pyridin-3-yl)piperidine-4-carboxylic acid(0.30 q), (S)-3-fluoropyrrolidine hydrochloride (0.13 g), HATU (0.39 g),DIPEA (0.37 mL) and DMF (3.0 mL) was stirred at room temperature for 18hr. The mixture was diluted with ethyl acetate and water, and extractedwith ethyl acetate. The organic layer was washed with water andsaturated brine, and dried over anhydrous sodium sulfate, and thesolvent was evaporated under reduced pressure. The residue was purifiedby silica gel column chromatography (NH, ethyl acetate/hexane), andcrystallized from ethyl acetate/heptane to give the title compound (0.31g).

¹H NMR (300 MHz, CDCl₃) δ 1.73-2.59 (7H, m), 2.68-2.85 (2H, m),3.06-3.21 (2H, m), 3.47-4.01 (4H, m), 5.14-5.44 (1H, m), 7.59 (1H, d,J=5.3 Hz), 7.69 (1H, s), 8.39 (1H, d, J=5.3 Hz), 8.46 (1H, s), 8.61 (1H,s).

Example 319(1-(4-(4-bromo-1H-pyrazol-1-yl)pyridin-3-yl)piperidin-4-yl)(3-fluoroazetidin-1-yl)methanone

A mixture of1-(4-(4-bromo-1H-pyrazol-1-yl)pyridin-3-yl)piperidine-4-carboxylic acid(0.078 g), 3-fluoroazetidine hydrochloride (0.025 g), HATU (0.11 g),triethylamine (0.12 mL) and DMF (1.0 mL) was stirred at room temperaturefor 3 hr. To the mixture was added water, and the mixture was extractedwith ethyl acetate. The organic layer was washed with water andsaturated brine, and dried over anhydrous magnesium sulfate, and thesolvent was evaporated under reduced pressure. The residue was purifiedby silica gel column chromatography (NH, ethyl acetate/hexane), andcrystallized from ethyl acetate/hexane to give the title compound (0.052g).

¹H NMR (300 MHz, CDCl₃) δ 1.68-2.03 (4H, m), 2.17-2.37 (1H, m),2.64-2.84 (2H, m), 3.03-3.19 (2H, m), 4.02-4.53 (4H, m), 5.15-5.49 (1H,m), 7.59 (1H, d, J=5.3 Hz), 7.69 (1H, s), 8.39 (1H, d, J=5.3 Hz), 8.44(1H, s), 8.59 (1H, s).

Example 322(1-(4-(4-cyclopropyl-1H-pyrazol-1-yl)pyridin-3-yl)piperidin-4-yl)((3S)-3-fluoropyrrolidin-1-yl)methanone

A mixture of(S)-(1-(4-(4-bromo-1H-pyrazol-1-yl)pyridin-3-yl)piperidin-4-yl)(3-fluoropyrrolidin-1-yl)methanone(0.10 g), potassium carbonate (0.13 g),bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II)(0.017 g), cyclopropyl trifluoroborate potassium salt (0.11 g), toluene(2.0 mL) and water (0.40 mL) was stirred with microwave irradiation at110° C. for 12 hr. The mixture was purified by silica gel columnchromatography (NH, ethyl acetate/hexane) and HPLC (C18, mobile phase:water/acetonitrile (containing 0.1% TFA)). The obtained fractions wereconcentrated, the residue was neutralized with aqueous sodium hydrogencarbonate solution, and the mixture was extracted with ethyl acetate.The organic layer was washed with water and saturated brine, dried overanhydrous sodium sulfate, and the solvent was evaporated under reducedpressure to give the title compound (0.046 g).

¹H NMR (300 MHz, CDCl₃) δ 0.55-0.66 (2H, m), 0.87-0.99 (2H, m),1.70-2.57 (8H, m), 2.65-2.83 (2H, m), 3.07-3.21 (2H, m), 3.46-4.01 (4H,m), 5.13-5.45 (1H, m), 7.48-7.71 (2H, m), 8.32-8.64 (3H, m).

Example 323(1-(4-(4-cyclopropyl-1H-pyrazol-1-yl)pyridin-3-yl)piperidin-4-yl)(3-fluoroazetidin-1-yl)methanone

A mixture of(1-(4-(4-bromo-1H-pyrazol-1-yl)pyridin-3-yl)piperidin-4-yl)(3-fluoroazetidin-1-yl)methanone(0.10 g), potassium carbonate (0.14 g),bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II)(0.017 g), cyclopropyl trifluoroborate potassium salt (0.11 g), toluene(2.0 mL) and water (0.40 mL) was stirred with microwave irradiation at110° C. for 12 hr. The mixture was purified by silica gel columnchromatography (NH, ethyl acetate/hexane) and HPLC (C18, mobile phase:water/acetonitrile (containing 0.1% TFA)). The obtained fractions wereconcentrated, the residue was neutralized with aqueous sodium hydrogencarbonate solution, and the mixture was extracted with ethyl acetate.The organic layer was washed with water and saturated brine, dried overanhydrous sodium sulfate, and the solvent was evaporated under reducedpressure to give the title compound (0.045 g).

¹H NMR (300 MHz, CDCl₃) δ 0.56-0.63 (2H, m), 0.88-0.97 (2H, m),1.67-2.00 (5H, m), 2.21-2.33 (1H, m), 2.63-2.80 (2H, m), 3.05-3.18 (2H,m), 4.04-4.52 (4H, m), 5.18-5.50 (1H, m), 7.46-7.73 (2H, m), 8.30-8.61(3H, m).

The compounds of Examples produced according to the above-mentionedmethods or a method analogous thereto are shown in the following tables.MS in the tables means actual measured value.

TABLE 1-1 EXAMPLE IUPACNAME Structure MS 1 1-(4-(4-chloro-1H-pyrazol-1-yl)pyridin-3-yl)-N,N- dimethyl)piperidine-4-carboxamide

334.2 2 N,N-dimethyl-1-(4-(5-methyl-1,3- oxazol-2-yl)pyridin-3-yl)piperidine-4-carboxamide

315.2 3 N-cyclopropyl-4-fluoro-1-(4-(4- methyl-1H-pyrazol-1-yl)pyrimidin-5-yl)piperidine-4- carboxamide

345.2 4 N-(cyclopropylmethyl)-4-fluoro- 1-(4-(4-methyl-1H-pyrazol-1-yl)pyrimidin-5-yl)piperidine-4- carboxamide

359.2 5 4-fluoro-N-(4-fluorobenzyl)-1- (4-(4-methyl-1H-pyrazol-1-yl)pyrimidin-5-yl)piperidine-4- carboxamide

413.2 6 N,N-dimethyl-1-(4-(2-methyl-1,3- oxazol-4-yl)pyridin-3-yl)piperidine-4-carboxamide

315.2 7 3-oxa-6-azabicyclo[3.1.1]hept-6-yl(1-(4-(4-(trifluoromethyl)-1H- pyrazol-1-yl)pyridin-3-yl)piperidin-4-yl)methanone

422.1 8 N-cyclopropyl-1-(4-(4- (trifluoromethyl)-1H-pyrazol-1-yl)pyridin-3-yl)piperidine-4- carboxamide

380.2 9 N-(cyclopropylmethyl)-1-(4-(4- (trifluoromethyl)-1H-pyrazol-1-yl)pyridin-3-yl)piperidine-4- carboxamide

394.2 10  N,N-dimethyl-1-(4-(4-methyl-1,3- thiazol-2-yl)pyridin-3-yl)piperidine-4-carboxamide

331.2

TABLE 1-2 EXAMPLE IUPACNAME Structure MS 11N,N-dimethyl-1-(4-(4-methyl-1,3- oxazol-2-yl)pyridin-3-yl)piperidine-4-carboxamide

316.2 12 N-methyl-1-(4-(4- (trifluoromethyl)-1H-pyrazol-1-yl)pyridin-3-yl)piperidine-4- carboxamide

354.1 13 (3-exo)-N,N-dimethyl-8-(4-(4- methyl-1H-pyrazol-1-yl)pyridin-3-yl)-8-azabicyclo[3.2.1]octane- 3-carboxamide

340.2 14 N-(cyclopropylmethyl)-3,3- difluoro-1-(4-(4-methyl-1H-pyrazol-1-yl)pyridin-3- yl)piperidine-4-carboxamide

376.1 15 3,3-difluoro-N-methyl-1-(4-(4- methyl-1H-pyrazol-1-yl)pyridin-3-yl)piperidine-4-carboxamide

336.1 16 (3,3-difluoroazetidin-1-yl)(3,3- difluoro-1-(4-(4-methyl-1H-pyrazol-1-yl)pyridin-3- yl)piperidin-4-yl)methanone

398.1 17 (3,3-difluoro-1-(4-(4-methyl-1H- pyrazol-1-yl)pyridin-3-yl)piperidin-4-yl)(3-oxa-6- azabicyclo[3.1.1]hept-6- yl)methanone

404.2 18 1-(4-(2H-indazol-2-yl)pyridin-3- yl)-N,N-dimethylpiperidine-4-carboxamide

350.2 19 N-cyclopropyl-1-(5-fluoro-4-(3- methyl-1H-pyrazol-1-yl)pyridin-3-yl)piperidine-4-carboxamide

344.2 20 1-(5-fluoro-4-(3-methyl-1H- pyrazol-1-yl)pyridin-3-yl)-N,N-dimethylpiperidine-4-carboxamide

332.3

TABLE 1-3 EXAMPLE IUPACNAME Structure MS 21 1-(4-(1,3-benzothiazol-2-yl)pyridin-3-yl)-N,N- dimethyl)piperidine-4-carboxamide

367.1 22 N,N-dimethyl-1-(4-(5-methyl- 1,3,4-thiadiazol-2-yl)pyridin-3-yl)piperidine-4-carboxamide

332.2 23 1-(4-(4-chloro-1H-pyrazol-1- yl)pyridin-3-yl)-N-cyclopropylpiperidine-4- carboxamide

346.2 24 1-(4-(4-chloro-1H-pyrazol-1- yl)pyridin-3-yl)-N-(tetrahydro-2H-pyran-4-yl)piperidine-4- carboxamide

390.1 25 (1-(4-(4-chloro-1H-pyrazol-1- yl)pyridin-3-yl)piperidin-4-yl)(2-methylpyrrolidin-1- yl)methanone

374.1 26 (1-(4-(4-chloro-1H-pyrazol-1- yl)pyridin-3-yl)piperidin-4-yl)(2,2-dimethylpyrrolidin-1- yl)methanone

388.1 27 1-(4-(4-chloro-1H-pyrazol-1- yl)pyridin-3-yl)-N-(cyclopropylmethyl)piperidine-4- carboxamide

360.1 28 1-(4-(4-chloro-1H-pyrazol-1- yl)pyridin-3-yl)-N-(oxetan-3-yl)piperidine-4-carboxamide

362.1 29 (1-(4-(4-chloro-1H-pyrazol-1- yl)pyridin-3-yl)piperidin-4-yl)(2-isopropylpyrrolidin-1- yl)methanone

402.1 30 (1-(4-(4-chloro-1H-pyrazol-1- yl)pyridin-3-yl)piperidin-4-yl)(1,1-dioxidothiomorpholin-4- yl)methanone

424.0

TABLE 1-4 EXAMPLE IUPACNAME Structure MS 31 1-(4-(4-chloro-1H-pyrazol-1-yl)pyridin-3-yl)-N-((3- methyloxetan-3- yl)methyl)piperidine-4-carboxamide

390.2 32 (1-(4-(4-chloro-1H-pyrazol-1- yl)pyridin-3-yl)piperidin-4-yl)(2-methylazetidin-1- yl)methanone

360.1 33 (2R)-1-((1-(4-(4-chloro-1H- pyrazol-1-yl)pyridin-3-yl)piperidin-4- yl)carbonyl)pyrrolidine-2- carbonitrile

385.1 34 1-(4-(4-chloro-1H-pyrazol-1- yl)pyridin-3-yl)-N-(tetrahydrofuran-3- yl)piperidine-4-carboxamide

376.1 35 (1-(4-(4-chloro-1H-pyrazol-1- yl)pyridin-3-yl)piperidin-4-yl)(3-oxa-6- azabicylco[3.1.1]hept-6- yl)methanone

388.1 36 1-(4-(4-chloro-1H-pyrazol-1- yl)pyridin-3-yl)-N-cyclopropyl-3,3-difluoropiperidine-4- carboxamide

382.1 37 1-(4-(4-chloro-1H-pyrazol-1- yl)pyridin-3-yl)-N-cyclobutyl-3,3-difluoropiperidine-4- carboxamide

396.2 38 1-(4-(4-chloro-1H-pyrazol-1- yl)pyridin-3-yl)-N-cyclopentyl-3,3-difluoropiperidine-4- carboxamide

410.1 39 1-(4-(4-chloro-1H-pyrazol-1- yl)pyridin-3-yl)-3,3-difluoro-N,N-dimethylpiperidine-4- carboxamide

370.0 40 (1-(4-(4-chloro-1H-pyrazol-1- yl)pyridin-3-yl)piperidin-4-yl)(2-ethylpyrrolidin-1- yl)methanone

388.2

TABLE 1-5 EXAMPLE IUPACNAME Structure MS 41 1-(4-(4-chloro-1H-pyrazol-1-yl)pyridin-3-yl)-N-(2,2- difluorocyclopropyl)piperidine- 4-carboxamide

382.1 42 N-cyclopropyl-3,3-difluoro-1-(4- (5-methyl-1,3-thiazol-2-yl)pyridin-3-yl)piperidine-4- carboxamide

379.2 43 1-(4-(4-bromo-1H-pyrazol-1- yl)pyridin-3-yl)-N,N-dimethylpiperidine-4-carboxamide

378.1 44 (1-(4-(4-chloro-1H-pyrazol-1- yl)pyridin-3-yl)piperidin-4-yl)(3-methoxypyrrolidin-1- yl)methanone

390.2 45 1-(4-(4-chloro-1H-pyrazol-1- yl)pyridin-3-yl)-N-cyclobutylpiperidine-4- carboxamide

360.1 46 (1-(4-(4-chloro-1H-pyrazol-1- yl)pyridin-3-yl)piperidin-4-yl)(3-methylmorpholin-4- yl)methanone

390.2 47 (1-(4-(4-chloro-1H-pyrazol-1- yl)pyridin-3-yl)piperidin-4-yl)(8-oxa-3- azabicyclo[3.2.1]oct-3- yl)methanone

402.1 48 (1-(4-(4-chloro-1H-pyrazol-1- yl)pyridin-3-yl)piperidin-4-yl)(3,3-difluoroazetidin-1- yl)methanone

382.1 49 (1-(4-(4-chloro-1H-pyrazol-1- yl)pyridin-3-yl)piperidin-4-yl)((1S,4S)-2-oxa-5- azabicyclo[2.2.1]hept-5- yl)methanone

388.1 50 (1-(4-(4-chloro-1H-pyrazol-1- yl)pyridin-3-yl)piperidin-4-yl)((2R,6S)-2,6- dimethylmorpholin-4-yl)methanone

404.2

TABLE 1-6 EXAMPLE IUPACNAME Structure MS 51 1-(4-(4-chloro-1H-pyrazol-1-yl)pyridin-3-yl)-N-cyclopropyl- N-ethylpiperidine-4-carboxamide

374.1 52 (1-(4-(4-chloro-1H-pyrazol-1- yl)pyridin-3-yl)piperidin-4-yl)(4,4-difluoropiperidin-1- yl)methanone

410.3 53 (1-(4-(4-chloro-1H-pyrazol-1- yl)pyridin-3-yl)piperidin-4-yl)(3-oxa-8- azabicylco[3.2.1]oct-8 yl)methanone

402.1 54 1-(4-(4-chloro-1H-pyrazol-1- yl)pyridin-3-yl)-N-methyl-N-(tetrahydro-2H-pyran-4- yl)piperidine-4-carboxamide

404.2 55 (1-(4-(4-chloro-1H-pyrazol-1- yl)pyridin-3-yl)piperidin-4-yl)(3,5-dimethylmorpholin-4- yl)methanone

404.2 56 1-(4-(4-chloro-1H-pyrazol-1- yl)pyridin-3-yl)-N-cyclopentylpiperidine-4- carboxamide

374.1 57 (1-(4-(4-chloro-1H-pyrazol-1- yl)pyridin-3-yl)piperidin-4-yl)(3,3-difluoropyrrolidin-1- yl)methanone

396.2 58 1-(4-(4-chloro-1H-pyrazol-1- yl)pyridin-3-yl)-N-cyclopropyl-N-methylpiperidine-4-carboxamide

360.1 59 1-(4-(4-cyclopropyl-1H-pyrazol- 1-yl)pyridin-3-yl)-N,N-dimethylpiperidine-4-carboxamide

340.3 60 (1-(4-(4-chloro-1H-pyrazol-1- yl)pyridin-3-yl)piperidin-4-yl)(6-oxa-3- azabicyclo[3.1.1]hept-3- yl)methanone

388.1

TABLE 1-7 EXAMPLE IUPACNAME Structure MS 61(1-(4-(4-chloro-1H-pyrazol-1- yl)pyridin-3-yl)piperidin-4-yl)(2-methylmorpholin-4- yl)methanone

390.2 62 1-(4-(4-chloro-1H-pyrazol-1- yl)pyridin-3-yl)-N-methylpiperidine-4-carboxamide

320.1 63 (1-(4-(4-chloro-1H-pyrazol-1- yl)pyridin-3-yl)piperidin-4-yl)(3-hydroxy-3- methylpyrrolidin-1-yl)methanone

390.2 64 1-(4-(4-chloro-1H-pyrazol-1- yl)pyridin-3-yl)-N-methyl-N-(1-methylpyrrolidin-3- yl)piperidine-4-carboxamide

403.2 65 3,3-difluoro-N,N-dimethyl-1-(4- (5-methyl-1,3-thiazol-2-yl)pyridin-3-yl)piperidine-4- carboxamide

367.1 66 (1-(4-(4-chloro-1H-pyrazol-1- yl)pyridin-3-yl)piperidin-4-yl)((1R,4R)-2-oxa-5- azabicyclo[2.2.1]hept-5- yl)methanone

388.2 67 azetidin-1-yl(1-(4-(4-chloro-1H- pyrazol-1-yl)pyridin-3-yl)piperidin-4-yl)methanone

346.2 68 1-(4-(4-methyl-1H-pyrazol-1- yl)pyridin-3-yl)-N-(tetrahydro-2H-pyran-4-yl)piperidine-4- carboxamide

370.2 69 (1,1-dioxidothiomorpholin-4- yl)(1-(4-(4-methyl-1H-pyrazol-1-yl)pyridin-3-yl)piperidin-4- yl)methanone

404.2 70 (2R)-1-((1-(4-(4-methyl-1H- pyrazol-1-yl)pyridin-3-yl)piperidin-4- yl)carbonyl)pyrrolidine-2- carbonitrile

365.2

TABLE 1-8 EXAMPLE IUPACNAME Structure MS 71(1-(4-(4-methyl-1H-pyrazol-1- yl)pyridin-3-yl)piperidin-4- yl)(3-oxa-8-azabicyclo[3.2.1]oct-8- yl)methanone

382.2 72 1-((1-(4-(4-methyl-1H-pyrazol-1- yl)pyridin-3-yl)piperidin-4-yl)carbonyl)pyrrolidine-3- carbonitrile

365.2 73 1-(4-(4-methyl-1H-pyrazol-1- yl)pyridin-3-yl)-N-phenylpiperidine-4-carboxamide

360.0 74 (2R)-1-(((4R)-1-(4-(4-chloro-1H-pyrazol-1-yl)pyridin-3-yl)-3,3- difluoropiperidin-4-yl)carbonyl)pyrrolidine-2- carbonitrile

421.1 75 (2R)-1-(((4S)-1-(4-(4-chloro-1H-pyrazol-1-yl)pyridin-3-yl)-3,3- difluoropiperidin-4-yl)carbonyl)pyrrolidine-2- carbonitrile

421.1 76 (1-(4-(4-chloro-1H-pyrazol-1- yl)pyridin-3-yl)-3,3-difluoropiperidin-4-yl)((1S,4S)- 2-oxa-5-azabicyclo[2.2.1]hept-5-yl)methanone

424.1 77 (1-(4-(4-chloro-1H-pyrazol-1- yl)pyridin-3-yl)-3,3-difluoropiperidin-4- yl)(morpholin-4-yl)methanone

412.2 78 (1-(4-(4-chloro-1H-pyrazol-1- yl)pyridin-3-yl)-3,3-difluoropiperidin-4-yl)(1,1- dioxidothiomorpholin-4- yl)methanone

460.1 79 1-(4-(4-chloro-1H-pyrazol-1- yl)pyridin-3-yl)-3,3-difluoro-N-(tetrahydro-2H-pyran-4- yl)piperidine-4-carboxamide

426.1 80 (1-(4-(4-chloro-1H-pyrazol-1- yl)pyridin-3-yl)piperidin-4-yl)(morpholin-4-yl)methanone

376.1

TABLE 1-9 EXAMPLE IUPACNAME Structure MS 81(1-(4-(4-chloro-1H-pyrazol-1- yl)pyridin-3-yl)piperidin-4-yl)(pyrrolidin-1-yl)methanone

360.1 82 2-methyl-8-(4-(4-methyl-1H- pyrazol-1-yl)pyridin-3-yl)-2,8-diazaspiro[4.5]decan-1-one

326.3 83 1-(4-(4-cyano-1H-pyrazol-1- yl)pyridin-3-yl)-N,N-dimethylpiperidine-4-carboxamide

325.2 84 (3,3-difluoropyrrolidin-1-yl)(1- (4-(4-methyl-1H-pyrazol-1-yl)pyridin-3-yl)piperidin-4- yl)methanone

376.1 85 (3,3-difluoroazetidin-1-yl)(1- (4-(4-methyl-1H-pyrazol-1-yl)pyridin-3-yl)piperidin-4- yl)methanone

362.1 86 N-cyclopropyl-N-methyl-1-(4-(4- methyl-1H-pyrazol-1-yl)pyridin-3-yl)piperidine-4-carboxamide

340.2 87 (2R)-1-((1-(4-(5-methyl-1,3,4- thiadiazol-2-yl)pyridin-3-yl)piperidin-4- yl)carbonyl)pyrrolidine-2- carbonitrile

383.1 88 (2-methylpyrrolidin-1-yl)(1-(4- (5-methyl-1,3,4-thiadazol-2-yl)pyridin-3-yl)piperidin-4- yl)methanone

372.2 89 (2,2-dimethylpyrrolidin-1-yl)(1-(4-(5-methyl-1,3,4-thiadiazol-2- yl)pyridin-3-yl)piperidin-4-yl)methanone

386.2 90 N-cyclopropyl-N-methyl-1-(4-(5- methyl-1,3,4-thiadiazol-2-yl)pyridin-3-yl)piperidine-4- carboxamide

358.1

TABLE 1-10 EXAMPLE IUPACNAME Structure MS 91(3,3-difluoropyrrolidin-1-yl)(1- (4-(5-methyl-1,3,4-thiadiazol-2-yl)pyridin-3-yl)piperidin-4- yl)methanone

394.2 92 (1-(4-(4-chloro-1H-pyrazol-1- yl)pyridin-3-yl)-3,3-difluoropiperidin-4-yl)(8-oxa-3- azabicyclo[3.2.1]oct-3- yl)methanone

438.1 93 (1-(4-(4-chloro-1H-pyrazol-1- yl)pyridin-3-yl)-3,3-difluoropiperidin-4-yl)(6-oxa-3- azabicyclo[3.1.1]hept-3- yl)methanone

424.2 94 (4S)-1-(4-(4-chloro-1H-pyrazol- 1-yl)pyridin-3-yl)-N-cyclopropyl-3,3- difluoropiperidine-4-carboxamide

382.1 95 (4R)-1-(4-(4-chloro-1H-pyrazol- 1-yl)pyridin-3-yl)-N-cyclopropyl-3,3- difluoropiperidine-4-carboxamide

382.1 96 1-(4-(4-chloro-1H-pyrazol-1- yl)pyridin-3-yl)-3,3-difluoro-N,N-dimethylpiperidine-4- carboxamide

370.0 97 1-(4-(4-chloro-1H-pyrazol-1- yl)pyridin-3-yl)-3,3-difluoro-N,N-dimethylpiperidine-4- carboxamide

370.1 98 N-cyclopropyl-4-fluoro-1-(4-(4- methyl-1H-pyrazol-1-yl)pyridin-3-yl)piperidine-4-carboxamide

344.2 99 4-fluoro-N-methyl-1-(4-(4- methyl-1H-pyrazol-1-yl)pyridin-3-yl)piperidine-4-carboxamide

318.2 100 (1-(4-(4-chloro-1H-pyrazol-1- yl)pyridin-3-yl)-3,3-difluoropiperidin-4-yl)(3-oxa-8- azabicylco[3.2.1]oct-8- yl)methanone

438.1

TABLE 1-11 EXAMPLE IUPACNAME Structure MS 1011-(4-(4-chloro-1H-pyrazol-1- yl)pyridin-3-yl)-3,3-difluoro-N-methyl-N-(tetrahydro-2H-pyran-4- yl)piperidine-4-carboxamide

440.1 102 4-((1-(4-(4-chloro-1H-pyrazol-1- yl)pyridin-3-yl)piperidin-4-yl)carbonyl)piperazin-2-one

389.1 103 (1-(4-(4-chloro-1H-pyrazol-1- yl)pyridin-3-yl)piperidin-4-yl)(4-methylpiperazin-1- yl)methanone

389.2 104 (3-methoxypyrrolidin-1-yl)(1-(4- (4-methyl-1H-pyrazol-1-yl)pyridin-3-yl)piperidin-4- yl)methanone

370.2 105 (1-(4-(4-methyl-1H-pyrazol-1- yl)pyridin-3-yl)piperidin-4-yl)(2-methylpyrrolidin-1- yl)methanone

354.2 106 (1-(4-(4-methyl-1H-pyrazol-1- yl)pyridin-3-yl)piperidin-4-yl)(3,3,4,4- tetrafluoropyrrolidin-1- yl)methanone

412.2 107 4-((1-(4-(4-chloro-1H-pyrazol-1- yl)pyridin-3-yl)piperidin-4-yl)carbonyl)-1-methylpiperazin- 2-one

403.1 108 methyl 1-((1-(4-(4-chloro-1H- pyrazol-1-yl)pyridin-3-yl)piperidin-4-yl)carbonyl)-L- prolinate

418.2 109 methyl 1-((1-(4-(4-chloro-1H- pyrazol-1-yl)pyridin-3-yl)piperidin-4-yl)carbonyl)-D- prolinate

418.2 110 (1-(4-(4-chloro-1H-pyrazol-1- yl)pyridin-3-yl)-3,3-difluoropiperidin-4-yl)(3,3- difluoropyrrolidin-1- yl)methanone

432.1

TABLE 1-12 EXAMPLE IUPACNAME Structure MS 111(1-(4-(4-chloro-1H-pyrazol-1- yl)pyridin-3-yl)piperidin-4-yl)((2S)-2-(2-hydroxypropan-2- yl)pyrrolidin-1-yl)methanone

418.2 112 (1-(4-(4-chloro-1H-pyrazol-1- yl)pyridin-3-yl)piperidin-4-yl)((2R)-2-(2-hydroxypropan-2- yl)pyrrolidin-1-yl)methanone

418.2 113 methyl 2-methyl-1-((1-(4-(4- methyl-1H-pyrazol-1-yl)pyridin-3-yl)piperidin-4-yl)carbonyl)-D- prolinate

412.3 114 1-((1-(4-(4-methyl-1H-pyrazol-1- yl)pyridin-3-yl)piperidin-4-yl)carbonyl)-1-prolinamide

383.2 115 (1-(4-(4-chloro-1H-pyrazol-1- yl)pyridin-3-yl)piperidin-4-yl)((2S)-2- (methoxymethyl)pyrrolidin-1- yl)methanone

404.2 116 (1-(4-(4-chloro-1H-pyrazol-1- yl)pyridin-3-yl)piperidin-4-yl)((2R)-2- (methoxymethyl)pyrrolidin-1- yl)methanone

404.2 117 1-((1-(4-(4-chloro-1H-pyrazol-1- yl)pyridin-3-yl)piperidin-4-yl)carbonyl)-4,4-difluoro-L- prolinamide

439.2 118 4,4-difluoro-1-((1-(4-(4-methyl- 1H-pyrazol-1-yl)pyridin-3-yl)piperidin-4-yl)carbonyl)-L- prolinamide

419.2 119 (2S)-1-((1-(4-(4-chloro-1H- pyrazol-1-yl)pyridin-3-yl)piperidin-4-yl)carbonyl)-4,4- difluoropyrrolidine-2- carbonitrile

421.1 120 (2S)-1-((1-(4-(4-methyl-1H- pyrazol-1-yl)pyridin-3-yl)piperidin-4- yl)carbonyl)pyrrolidine-2- carbonitrile

365.2

TABLE 1-13 EXAMPLE IUPACNAME Structure MS 121(2S)-4,4-difluoro-1-((1-(4-(4- methyl-1H-pyrazol-1-yl)pyridin-3-yl)piperidin-4- yl)carbonyl)pyrrolidine-2- carbonitrile

401.2 122 (1-(4-(5-methyl-1,3,4- thiadiazol-2-yl)pyridin-3-yl)piperidin-4-yl)(3-oxa-8- azabicyclo[3.2.1]oct-8- yl)methanone

400.1 123 (1-(4-(5-methyl-1,3,4- thiadiazol-2-yl)pyridin-3-yl)piperidin-4-yl)(3,3,4,4- tetrafluoropyrrolidin-1- yl)methanone

430.1 124 1-((1-(4-(4-methyl-1H-pyrazol-1- yl)pyridin-3-yl)piperidin-4-yl)carbonyl)-D-prolinamide

383.2 125 2-methyl-1-((1-(4-(4-methyl-1H- pyrazol-1-yl)pyridin-3-yl)piperidin-4-yl)carbonyl)-D- prolinamide

397.2 126 2-methyl-1-((1-(4-(5-methyl- 1,3,4-thiadiazol-2-yl)pyridin-3-yl)piperidin-4-yl)carbonyl)-D- prolinamide

415.2 127 (2R)-2-methyl-1-((1-(4-(4- methyl-1H-pyrazol-1-yl)pyridin-3-yl)piperidin-4- yl)carbonyl)pyrrolidine-2- carbonitrile

379.3 128 (2R)-2-methyl-1-((1-(4-(5- methyl-1,3,4-thiadiazol-2-yl)pyridin-3-yl)piperidin-4- yl)carbonyl)pyrrolidine-2- carbonitrile

397.2 129 (2R)-1-((1-(4-(5-methyl-1,3- thiazol-2-yl)pyridin-3-yl)piperidin-4- yl)carbonyl)pyrrolidine-2- carbonitrile

382.1 130 (2R)-4,4-difluoro-1-((1-(4-(4- methyl-1H-pyrazol-1-yl)pyridin-3-yl)piperidin-4- yl)carbonyl)pyrrolidine-2- carbonitrile

401.2

TABLE 1-14 EXAMPLE IUPACNAME Structure MS 131 (2R)-1-((4-fluoro-1-(4-(5-methyl-1,3,4-thiadiazol-2- yl)pyridin-3-yl)piperidin-4-yl)carbonyl)pyrrolidine-2- carbonitrile

401.1 132 (2R)-4,4-difluoro-1-((1-(4-(5- methyl-1,3,4-thiadiazol-2-yl)pyridin-3-yl)piperidin-4- yl)carbonyl)pyrrolidine-2- carbonitrile

419.1 133 ((2R)-2- (methoxymethyl)pyrrolidin-1-yl)(1-(4-(5-methyl-1,3,4- thiadiazol-2-yl)pyridin-3-yl)piperidin-4-yl)methanone

402.1 134 (2R,4S)-4-hydroxy-1-((1-(4-(4- methyl-1H-pyrazol-1-yl)pyridin-3-yl)piperidin-4- yl)carbonyl)pyrrolidine-2- carbonitrile

381.2 135 (2R,4S)-1-((1-(4-(4-chloro-1H- pyrazol-1-yl)pyridin-3-yl)piperidin-4-yl)carbonyl)-4- hydroxypyrrolidine-2- carbonitrile

401.1 136 (2R,4R)-4-hydroxy-1-((1-(4-(4- methyl-1H-pyrazol-1-yl)pyridin-3-yl)piperidin-4- yl)carbonyl)pyrrolidine-2- carbonitrile

381.1 137 (2R,4R)-1-((1-(4-(4-chloro-1H- pyrazol-1-yl)pyridin-3-yl)piperidin-4-yl)carbonyl)-4- hydroxyprrolidine-2- carbonitrile

401.1 138 (2R,4R)-4-methoxy-1-((1-(4-(4- methyl-1H-pyrazol-1-yl)pyridin-3-yl)piperidin-4- yl)carbonyl)pyrrolidine-2- carbonitrile

395.3 139 (2R,4R)-1-((1-(4-(4-chloro-1H- pyrazol-1-yl)pyridin-3-yl)piperidin-4-yl)carbonyl)-4- methoxypyrrolidine-2- carbonitrile

415.2 140 (2R,4R)-4-methoxy-1-((1-(4-(5- methyl-1,3,4-thiadiazol-2-yl)pyridin-3-yl)piperidin-4- yl)carbonyl)pyrrolidine-2- carbonitrile

413.2

TABLE 1-15 EXAMPLE IUPACNAME Structure MS 141(2R)-1-((1-(4-(2H-indazol-2- yl)pyridin-3-yl)piperidin-4-yl)carbonyl)pyrrolidine-2- carbonitrile

401.2 142 (2R)-1-((1-(2,4′-bipyridin-3′- yl)piperidin-4-yl)carbonyl)pyrrolidine-2- carbonitrile

362.2 143 (2R)-1-((1-(2,4′-bipyridin-3′-yl)piperidin-4-yl)carbonyl)-4,4- difluoropyrrolidine-2- carbonitrile

398.1 144 (2R,4S)-4-methoxy-1-((1-(4-(4- methyl-1H-pyrazol-1-yl)pyridin-3-yl)piperidin-4- yl)carbonyl)pyrrolidine-2- carbonitrile

395.3 145 2-(4-methoxyphenyl)-1-(4-(4- phenylpyridin-3-yl)piperazin-1-yl)ethanone

388.2 146 3-phenyl-1-(4-(4-phenylpyridin-3-yl)piperazin-1-yl)propan-1-one

372.2 147 2-cyclopropyl-1-(4-(4- phenylpyridin-3-yl)piperazin-1-yl)ethanone

322.2 148 2-cyclopropyl-1-(4-(4-(4- methylphenyl)pyridin-3-yl)piperazin-1-yl)ethanone

336.2 149 2-cyclopropyl-1-(4-(4-(4- fluorophenyl)pyridin-3-yl)piperazin-1-yl)ethanone

340.2 150 2-cyclopropyl-1-(4-(4-(1-methyl- 1H-pyrazol-4-yl)pyridin-3-yl)piperazin-1-yl)ethanone

326.3

TABLE 1-16 EXAMPLE IUPACNAME Structure MS 151 2-cyclopropyl-1-(4-(4-phenylpyrimidin-5-yl)piperazin- 1-yl)ethanone

323.2 152 cyclopropyl(4-(4-phenylpyridin- 3-yl)piperazin-1-yl)methanone

308.2 153 N-cyclopropyl-4-(4- phenylpyridin-3-yl)piperazine-1-carboxamide

323.2 154 2-cyclopropyl-1-(4-(4-(4-methyl- 1H-pyrazol-1-yl)pyridin-3-yl)piperazin-1-yl)ethanone

326.2 155 (3,3-difluoroazetidin-1-yl)(4-(4-phenylpyridin-3-yl)piperazin- 1-yl)methanone

359.1 156 (4-(4-phenylpyridin-3- yl)piperazin-1-yl)(tetrahydro-2H-pyran-4-yl)methanone

352.2 157 morpholin-4-yl(4-(4- phenylpyridin-3-yl)piperazin-1-yl)methanone

353.2 158 benzyl (2R)-2-methyl-4-(4- phenylpyrimidin-5-yl)piperazine-1-carboxylate

389.2 159 2-cyclopropyl-1-((2R)-2-methyl- 4-(4-phenylpyrimidin-5-yl)piperazin-1-yl)ethanone

337.2 160 tert-butyl (1S,4S)-5-(4- phenylpyridin-3-yl)-2,5-diazabicyclo[2.2.1]heptane-2- carboxylate

352.2

TABLE 1-17 EXAMPLE IUPACNAME Structure MS 1612-cyclopropyl-1-((1S,4S)-5-(4- phenylpyridin-3-yl)-2,5-diazabicyclo[2.2.1]hept-2- yl)ethanone

334.2 162 benzyl (2S)-2-methyl-4-(4- phenylpyrimidin-5-yl)piperazine-1-carboxylate

389.2 163 1-(4-(2,4′-hipyridin-3′- yl)piperazin-1-yl)-2-cyclopropylethanone

323.2 164 2-cyclopropyl-1-(4-(4-(3- fluorophenyl)pyridin-3-yl)piperazin-1-yl)ethanone

340.2 165 cyclopropyl(4-(5-fluoro-4- phenylpyridin-3-yl)piperazin-1-yl)methanone

326.2 166 2-cyclopropyl-1-(4-(5-fluoro-4-phenylpyridin-3-yl)piperazin-1- yl)ethanone

340.2 167 2-cyclopropyl-1-(-(4-(2- fluorophenyl)pyridin-3-yl)piperazin-1-yl)ethanone

340.2 168 1-(4-(4-(2-chlorophenyl)pyridin- 3-yl)piperazin-1-yl)-2-cyclopropylethanone

356.2 169 benzyl 4-(4-phenylpyrimidin-5- yl)piperazine-1-carboxylate

375.2 170 2-cyclopropyl-1-((2S)-2-methyl- 4-(4-phenylpyrimidin-5-yl)piperazin-1-yl)ethanone

337.2

TABLE 1-18 EXAMPLE IUPACNAME Structure MS 171 2-cyclopropyl-1-(4-(4-(1H-pyrazol-1-yl)pyridin-3- yl)piperazin-1-yl)ethanone

312.2 172 N-cyclopropyl-1-(4- phenylpyridin-3-yl)piperidine-4-carboxamide

322.2 173 tert-butyl 4-(4-phenylpyridin-3- yl)piperazine-1-carboxylate

340.2 174 2-phenoxy-1-(4-(4- phenylpyrimidin-5-yl)piperazin-1-yl)ethanone

375.2 175 N-benzyl-4-(4-phenylpyrimidin-5- yl)piperazine-1-carboxamide

374.2 176 N-ethyl-4-(4-phenylpyrimidin-6- yl)piperazine-1-carboxamide

312.2 177 N-methyl-4-(4-phenylpyrimidin-5- yl)piperazine-1-carboxamide

298.2 178 cyclopropyl(4-(4- phenylpyrimidin-5-yl)piperazin-1-yl)methanone

309.2 179 ((1S,2S)-2-phenylcyclopropyl)(4- (4-phenylpyrimidin-5-yl)piperazin-1-yl)methanone

385.1 180 N-cyclopropyl-1-(4- phenylpyrimidin-5-yl)piperidine-4-carboxamide

323.2

TABLE 1-19 EXAMPLE IUPACNAME Structure MS 1811-(2-oxo-2-(4-(4-phenylpyridin- 3-yl)piperazin-1-yl)ethyl)pyridin-2(1H)-one

375.1 182 1-(4-(4-phenylpyridin-3- yl)piperazin-1-yl)-2-(1H-pyrazol-1-yl)ethanone

348.2 183 3-(1H-indazol-1-yl)-1-(4-(4- phenylpyridin-3-yl)piperazin-1-yl)propan-1-one

412.6 184 4-oxo-4-(4-(4-phenylpyridin-3- yl)piperazin-1-yl)butanenitrile

321.1 185 phenyl (4-(4-phenylpyridin-3- yl)piperazin-1-yl)methanone

344.1 186 methyl 4-methyl-1-(4- phenylpyrimidin-5-yl)piperidine-4-carboxylate

312.2 187 N,N-dimethyl-1-(4- phenylpyrimidin-5-yl)piperidine-4-carboxamide

311.2 188 4-(4-phenylpyrimidin-5-yl)-N- (pyridin-2-ylmethyl)piperazine-1-carboxamide

375.2 189 N-cyclopropyl-1-(4-(4-methyl-1H- pyrazol-1-yl)pyridin-3-yl)piperidine-4-carboxamide

326.2 190 (2-(4-fluorophenyl)azetidin-1- yl)(4-(4-phenylpyridin-3-yl)piperazin-1-yl)methanone

417.1

TABLE 1-20 EXAMPLE IUPACNAME Structure MS 1914-(4-phenylpyridin-3-yl)-N- (2,2,2- trifluoroethyl)piperazine-1-carboxamide

365.0 192 8-oxa-3-azabicyclo[3.2.1]oct-3- yl(4-(4-phenylpyridin-3-yl)piperazin-1-yl)methanone

379.2 193 N-cyclopropyl-1-(4-(4- fluorophenyl)pyrimidin-5-yl)piperidine-4-carboxamide

341.2 194 N,N-dimethyl-1-(4-(4-methyl- 1H-pyrazol-1-yl)pyridin-3-yl)piperidine-4-carboxamide

314.3 195 azetidin-1-yl(1-(4-(4-methyl-1H- pyrazol-1-yl)pyridin-3-yl)piperidin-4-yl)methanone

326.2 196 1-(4-(4-fluorophenyl)pyrimidin-5-yl)-N,N-dimethylpiperidine-4- carboxamide

329.2 197 N-cyclopropyl-1-(4-(1H-pyrazol-1-yl)pyridin-3-yl)piperidine-4- carboxamide

312.2 198 (2R)-1-((4-(4-(4- fluorophenyl)pyrimidin-5- yl)piperazin-1-yl)carbonyl)pyrrolidine-2- carbonitrile

381.1 199 (4-(4-(4-fluorophenyl)pyrimidin-5-yl)piperazin-1-yl)(pyrrolidin- 1-yl)methanone

356.2 200 N-cyclopropyl-1-(4-(3,4- dimethyl-1H-pyrazol-1-yl)pyridin-3-yl)piperidine-4- carboxamide

340.3

TABLE 1-21 EXAMPLE IUPACNAME Structure MS 201N-methyl-1-(4-(4-methyl-1H- pyrazol-1-yl)pyridin-3-yl)piperidine-4-carboxamide

300.2 202 (1-(4-(4-methyl-1H-pyrazol-1- yl)pyridin-3-yl)piperidin-4-yl)(3-oxa-6- azabicyclo[3.1.1]hept-6- yl)methanone

368.2 203 1-(2,4′-bipyridin-3′-yl)-N- cyclopropylpiperidine-4-carboxamide

323.2 204 1-(2,4′-bipyridin-3′-yl)-N- methylpiperidine-4-carboxamide

297.2 205 1-(2,4′-bipyridin-3′-yl)-N,N- dimethylpiperidine-4-carboxamide

311.2 206 4-fluoro-1-(4-(4- fluorophenyl)pyrimidin-5-yl)piperidine-4-carboxamide

319.2 207 N-(4-fluorobenzyl)-4-(4-(4- fluorophenyl)pyrimidin-5-yl)piperazine-1-carboxamide

410.2 208 (3S)-N-ethyl-4-(4-(4- fluorophenyl)pyrimidin-5-yl)-3-methylpiperazine-1-carboxamide

344.2 209 (3S)-4-(4-(4- fluorophenyl)pyrimidin-5-yl)-N,N,3-trimethylpiperazine-1- carboxamide

344.2 210 N-cyclopropyl-1-(4-(4-methyl-1H- pyrazol-1-yl)pyridin-3-yl)-2-oxopiperidine-4-carboxamide

340.2

TABLE 1-22 EXAMPLE IUPACNAME Structure MS 2114-((3,3-difluoroazetidin-1- yl)carbonyl)-1-(4-(4-methyl-1H-pyrazol-1-yl)pyridin-3- yl)piperidin-2-one

376.1 212 N-(cyclobutylmethyl)-4-(4-(4- fluorophenyl)pyrimidin-5-yl)piperazine-1-carboxamide

370.2 213 (1-(2,4′-bipyridin-3′- yl)piperidin-4-yl)(3,3-difluoroazetidin-1-yl)methanone

359.1 214 (1-(2,4′-bipyridin-3′- yl)piperidin-4-yl)(3,3-difluoropyrrolidin-1- yl)methanone

373.2 215 (1-(2,4′-bipyridin-3′- yl)piperidin-4-yl)(3-oxa-6-azabicyclo[3.1.1]hept-6- yl)methanone

365.2 216 1-(2,4′-bipyridin-3′-yl)-N- cyclopropyl-N-ethylpiperidine-4-carboxamide

351.2 217 N-(cyclopropylmethyl)-4-(4-(4- methyl-1H-pyrazol-1-yl)pyridin-3-yl)piperazine-1-carboxamide

341.2 218 N-ethyl-4-(4-(4-metbyl-1H- pyrazol-1-yl)pyridin-3-yl)piperazine-1-carboxamide

315.3 219 N-(4-fluorobenzyl)-4-(4-(4- methyl-1H-pyrazol-1-yl)pyridin-3-yl)piperazine-1-carboxamide

395.3 220 8-(4-(4-fluorophenyl)pyrimidin-5-yl)-2,8-diazaspiro[4.5]decan- 1-one

327.2

TABLE 1-23 EXAMPLE IUPACNAME Structure MS 221N-cyclopropyl-1-(4-(4-methyl-1H- pyrazol-1-yl)pyrimidin-5-yl)piperidine-4-carboxamide

327.2 222 8-(4-(4-fluorophenyl)pyrimidin- 5-yl)-2-methyl-2,8-diazaspiro[4.5]decan-1-one

341.1 223 N,N-dimethyl-1-(4-(4-methyl-1H- pyrazol-1-yl)pyrimidin-5-yl)piperidine-4-carboxamide

315.3 224 (3,3-difluoroazetidin-1-yl)(1- (4-(4-methyl-1H-pyrazol-1-yl)pyrimidin-5-yl)piperidin-4- yl)methanone

363.2 225 N-cyclopropyl-1-(4-(4- (trifluoromethyl)phenyl)pyrimidin-5-yl)piperidine-4-carboxamide

391.2 226 N,N-dimethyl-1-(4-(4- (trifluoromethyl)phenyl)pyrimidin-5-yl)piperidine-4-carboxamide

379.2 227 (1R,5S,6r)-N-cyclopropyl-3-(4-(4-fluorophenyl)pyrimidin-5-yl)- 3-azabicyclo[3.1.0]hexane-6-carboxamide

339.2 228 (3,3-difluoroazetidin-1- yl)((1R,5S,6r)-3-(4-(4-fluorophenyl)pyrimidin-5-yl)-3- azabicyclo[3.1.0]hex-6- yl)methanone

375.1 229 N,N-dimethyl-1-(4-(4- (trifluoromethyl)-1H-pyrazol-1-yl)pyridin-3-yl)piperidine-4- carboxamide

368.1 230 N-(4-fluorobenzyl)-4-(4-(4- methyl-1H-pyrazol-1-yl)pyrimidin-5-yl)piperazine-1- carboxamide

396.2

TABLE 1-24 EXAMPLE IUPACNAME Structure MS 231N-(cyclopropylmethyl)-4-(4-(4- methyl-1H-pyrazol-1-yl)pyrimidin-5-yl)piperazine-1- carboxamide

342.2 232 N-ethyl-4-(4-(4-methyl-1H- pyrazol-1-yl)pyrimidin-5-yl)piperazine-1-carboxamide

316.2 233 (3,3-difluoroazetidin-1-yl)(1- (4-(2-methyl-1,3-thiazol-4-yl)pyridin-3-yl)piperidin-4- yl)methanone

379.2 234 N-cyclopropyl-1-(5-fluoro-4-(4-methyl-1H-pyrazol-1-yl)pyridin- 3-yl)piperidine-4-carboxamide

344.2 235 1-(5-fluoro-4-(4-methyl-1H- pyrazol-1-yl)pyridin-3-yl)-N,N-dimethylpiperidine-4-carboxamide

332.2 236 (3,3-difluoroazetidin-1-yl)(1- (5-fluoro-4-(4-methyl-1H-pyrazol-1-yl)pyridin-3- yl)piperidin-4-yl)methanone

380.2 237 N-cyclopropyl-3,3-difluoro-1-(4- (4-methyl-1H-pyrazol-1-yl)pyridin-3-yl)piperidine-4- carboxamide

362.1 238 3,3-difluoro-N,N-dimethyl-1-(4- (4-methyl-1H-pyrazol-1-yl)pyridin-3-yl)piperidine-4- carboxamide

350.1 239 (3,3-difluoroazetidin-1-yl)(1- (4-(3-methyl-1H-pyrazol-1-yl)pyrimidin-5-yl)piperidin-4- yl)methanone

363.2 240 N,N-dimethyl-1-(4-(3-methyl-1H- pyrazol-1-yl)pyrimidin-5-yl)piperidine-4-carboxamide

315.3

TABLE 1-25 EXAMPLE IUPACNAME Structure MS 241 (3R)-N-ethyl-4-(4-(4-fluorophenyl)pyrimidin-5-yl)-3- methylpiperazine-1-carboxamide

344.3 242 (3R)-N-(cyclopropylmethyl)-4-(4-(4-fluorophenyl)pyrimidin-5-yl)- 3-methylpiperazine-1-carboxamide

370.2 243 N,N-dimethyl-1-(4-(3-methyl-1H- pyrazol-1-yl)pyridin-3-yl)piperidine-4-carboxamide

314.3 244 1-(4-(4-ethyl-1H-pyrazol-1- yl)pyridin-3-yl)-N,N-dimethylpiperidine-4-carboxamide

328.2 245 (3,3-difluoroazetidin-1-yl)(1- (4-(2-methyl-1,3-oxazol-4-yl)pyridin-3-yl)piperidin-4- yl)methanone

363.2 246 N,N-dimethyl-1-(4-(5-methyl-1,3- thiazol-2-yl)pyridin-3-yl)piperidine-4-carboxamide

331.2 247 1-(4-(4-chloro-1H-pyrazol-1- yl)pyridin-3-yl)-N-(cyanomethyl)-N- methylpiperidine-4-carboxamide

359.1 248 N-(cyanomethyl)-N-methyl-1-(4- (4-methyl-1H-pyrazol-1-yl)pyridin-3-yl)piperidine-4- carboxamide

339.2 249 N-cyclopropyl-1-(4-(5-methyl- 1,3,4-thiadiazol-2-yl)pyridin-3-yl)piperidine-4-carboxamide

344.1 250 (2R)-1-((1-(4-(5-cyclopropyl- 1,3,4-thiadiazol-2-yl)pyridin-3-yl)piperidin-4- yl)carbonyl)pyrrolidine-2- carbonitrile

409.2

TABLE 1-26 EXAMPLE IUPACNAME Structure MS 251(2R,4S)-4-ethoxy-1-((1-(4-(5- methyl-1,3,4-thiadiazol-2-yl)pyridin-3-yl)piperidin-4- yl)carbonyl)pyrrolidine-2- carbonitrile

427.2 252 (2R,4S)-4-isopropoxy-1-((1-(4- (5-methyl-1,3,4-thiadiazol-2-yl)pyridin-3-yl)piperidin-4- yl)carbonyl)pyrrolidine-2- carbonitrile

441.1 253 (2R,4S)-4-methoxy-1-((1-(4-(5- methyl-1,3,4-thiadiazol-2-yl)pyridin-3-yl)piperidin-4- yl)carbonyl)pyrrolidine-2- carbonitrile

413.2 254 ((2R)-2- (methoxymethyl)pyrrolidin-1-yl)(1-(4-(4-metbyl-1H-pyrazol-1- yl)pyridin-3-yl)piperidin-4-yl)methanone

384.2 255 (2R)-1-((1-(4-(5-ethyl-1,3,4- thiadiazol-2-yl)pyridin-3-yl)piperidin-4- yl)carbonyl)pyrrolidine-2- carbonitrile

397.2

TABLE 1-27 EXAMPLE IUPACNAME Structure MS 256 3,7-dioxa-9-azabicyclo[3.3.1]non-9-yl(1-(4- (4-methyl-1H-pyrazol-1-yl)pyridin-3-yl)piperidin-4- yl)methanone

398.2 257 (2R,4S)-4-ethoxy-1-((1-(4-(4- methyl-1H-pyrazol-1-yl)pyridin-3-yl)piperidin-4- yl)carbonyl)pyrrolidine-2- carbonitrile

409.2 258 (2R,4S)-4-isopropoxy-1-((1-(4- (4-methyl-1H-pyrazol-1-yl)pyridin-3-yl)piperidin-4- yl)carbonyl)pyrrolidine-2- carbonitrile

423.2 259 (2R,4S)-4-(difluoromethoxy)-1- ((1-(4-(4-methyl-1H-pyrazol-1-yl)pyridin-3-yl)piperidin-4- yl)carbonyl)pyrrolidine-2- carbonitrile

431.1 260 (2R,4S)-4-(difluoromethoxy)-1- ((1-(4-(5-methyl-1,3,4-thiadiazol-2-yl)pyridin-3- yl)piperidin-4- yl)carbonyl)pyrrolidine-2-carbonitrile

449.0 261 methyl 5,5-dimethyl-1-((1-(4-(5- methyl-1,3,4-thiadiazol-2-yl)pyridin-3-yl)piperidin-4- yl)carbonyl)prolinate

444.2 262 N,N-dimethyl-1-((1-(4-(4- methyl-1H-pyrazol-1-yl) pyridin-3-yl)piperidin-4-yl)carbonyl)- D-prolinamide

41l.3 263 N,N-dimethyl-1-((1-(4-(5- methyl-1,3,4-thiadiazol-2-yl)pyridin-3- yl)piperidin-4-yl)carbonyl)- D-prolinamide

429.2 265 (5-(methoxymethyl)-2,2- dimethylpyrrolidin-1-yl)(1-(4-(5-methyl-1,3,4-thiadiazol-2- yl)pyridin-3-yl)piperidin-4- yl)methanone(optical isomer)

430.2

TABLE 1-28 EXAMPLE IUPACNAME Structure MS 266 (5-(methoxymethyl)-2,2-dimethylpyrrolidin-1-yl)(1-(4- (5-methyl-1,3,4-thiadiazol-2-yl)pyridin-3-yl)piperidin-4- yl)methanone (optical isomer)

430.2 267 5,5-dimethyl-1-((1-(4-(5-methyl-1,3,4-thiadiazol-2-yl)pyridin-3- yl)piperidin-4- yl)carbonyl)prolinamide(optical isomer)

429.2 268 5,5-dimethyl-1-((1-(4-(5-methyl-1,3,4-thiadiazol-2-yl)pyridin-3- yl)piperidin-4- yl)carbonyl)prolinamide(optical isomer)

429.2 269 N,N-dimethyl-1-(4-(1H-pyrazol-1- yl)pyridin-3-yl)piperidine-4-carboxamida

300.2 270 N-phenyl-1-(4-phenylpyrimidin-5- yl)piperidine-4-carboxamide

359.2 271 1-(4-phenylpyrimidin-5-yl)-N- (pyridin-2-ylmethyl)piperidine-4-carboxamide

374.2 272 (1-(4-phenylpyrimidin-5- yl)piperidin-4-yl)(piperidin-1-yl)methanone

351.2 273 (1-(4-(4-methyl-1H-pyrazol-1- yl)pyridin-3-yl)piperidin-4-yl)(piperidin-1-yl)methanone

354.2 274 (1-(4-(4-methyl-1H-pyrazol-1- yl)pyridin-3-yl)piperidin-4-yl)(pyrrolidin-1-yl)methanone

340.0 275 (1-(4-(4-methyl-1H-pyrazol-1- yl)pyridin-3-yl)piperidin-4-yl)(morpholin-4-yl)methanone

356.2

TABLE 1-29 EXAMPLE IUPACNAME Structure MS 276(3-methoxyazetidin-1-yl)(1-(4- (4-methyl-1H-pyrazol-1-yl)pyridin-3-yl)piperidin-4- yl)methanone

356.2 277 N-cyclopropyl-1-(4-(4- fluorophenyl)pyrimidin-5-yl)-N-methylpiperidine-4-carboxamide

355.2 278 (3-fluoroazetidin-1-yl)(1-(4-(4- fluorophenyl)pyrimidin-5-yl)piperidin-4-yl)methanone

359.2 279 N-(4-methoxybenzyl)-4-(4- phenylpyrimidin-5-yl)piperazine-1-carboxamide

404.2 280 (3-fluoroazetidin-1-yl)(1-(4-(4-methyl-1H-pyrazol-1-yl)pyridin- 3-yl)piperidin-4-yl)methanone

344.1 281 (1-(4-(4-chloro-1H-pyrazol-1- yl)pyridin-3-yl)piperidin-4-yl)(3-fluoroazetidin-1- yl)methanone

364.2 282 ((3S)-3-fluoropyrrolidin-1- yl)(1-(4-(4-methyl-1H-pyrazol-1-yl)pyridin-3-yl)piperidin-4- yl)methanone

358.1 283 ((3R)-3-fluoropyrrolidin-1- yl)(1-(4-(4-methyl-1H-pyrazol-1-yl)pyridin-3-yl)piperidin-4- yl)methanone

358.1 284 (1-(4-(4-chloro-1H-pyrazol-1- yl)pyridin-3-yl)piperidin-4-yl)((3S)-3-fluoropyrrolidin-1- yl)methanone

378.1 285 (1-(4-(4-chloro-1H-pyrazol-1- yl)pyridin-3-yl)piperidin-4-yl)((3R)-3-fluoropyrrolidin-1- yl)methanone

378.1

TABLE 1-30 EXAMPLE IUPACNAME Structure MS 286(1-(4-(4-fluorophenyl)pyrimidin- 5-yl)piperidin-4-yl)((3S)-3-fluoropyrrolidin-1-yl)methanone

373.1 287 (1-(4-(4-fluorophenyl)pyrimidin- 5-yl)piperidin-4-yl)((3R)-3-fluoropyrrolidin-1-yl)methanone

373.2 288 1-(4-(4-fluorophenyl)pyrimidin- 5-yl)-N-methyl-N-(tetrahydro-2H-pyran-4-yl)piperidine-4- carboxamide

399.1 289 1-(4-(4-fluorophenyl)pyrimidin-5-yl)-N-(tetrahydro-2H-pyran-4- yl)piperidine-4-carboxamide

383.1 290 1-(4-(4-fluorophenyl)pyrimidin-5-yl)-N-((3S)-tetrahydrofuran-3- yl)piperidine-4-carboxamide

368.9 291 1-(4-(4-fluorophenyl)pyrimidin-5-yl)-N-((3R)-tetrahydrofuran-3- yl)piperidine-4-carboxamide

368.9 292 1-(4-(4-methyl-1H-pyrazol-1- yl)pyridin-3-yl)-N-((3S)-tetrahydrofuran-3-yl)piperidine- 4-carboxamide

356.2 293 1-(4-(4-chloro-1H-pyrazol-1- yl)pyridin-3-yl)-N-((3S)-tetrahydrofuran-3-yl)piperidine- 4-carboxamide

376.1 294 1-(4-(4-methyl-1H-pyrazol-1- yl)pyridin-3-yl)-N-((3R)-tetrahydrofuran-3-yl)piperidine- 4-carboxamide

356.2 295 1-(4-(4-chloro-1H-pyrazol-1- yl)pyridin-3-yl)-N-((3R)-tetrahydrofuran-3-yl)piperidine- 4-carboxamide

376.1

TABLE 1-31 EXAMPLE IUPACNAME Structure MS 296N-methyl-1-(4-(4-methyl-1H- pyrazol-1-yl)pyridin-3-yl)-N-(tetrahydro-2H-pyran-4- yl)piperidine-4-carboxamide

384.2 297 N-(4-fluorobenzyl)-N-methyl-4- (4-(4-methyl-1H-pyrazol-1-yl)pyridin-3-yl)piperazine-1- carboxamide

409.2 298 N-benzyl-N-methyl-4-(4- phenylpyrimidin-5-yl)piperazine-1-carboxamide

388.1 299 (1-(4-(4-chloro-1H-pyrazol-1- yl)pyridin-3-yl)piperidin-4-yl)((3S)-3-methoxypyrrolidin-1- yl)methanone

390.1 300 (1-(4-(4-chloro-1H-pyrazol-1- yl)pyridin-3-yl)piperidin-4-yl)((3R)-3-methoxypyrrolidin-1- yl)methanone

390.1 301 ((3S)-3-methoxypyrrolidin-1- yl)(1-(4-(4-methyl-1H-pyrazol-1-yl)pyridin-3-yl)piperidin-4- yl)methanone

370.1 302 ((3R)-3-methoxypyrrolidin-1- yl)(1-(4-(4-methyl-1H-pyrazol-1-yl)pyridin-3-yl)piperidin-4- yl)methanone

370.1 303 (1-(4-(4-fluorophenyl)pyrimidin- 5-yl)piperidin-4-yl)((3S)-3-methoxypyrrolidin-1-yl)methanone

385.1 304 (1-(4-(4-fluorophenyl)pyrimidin- 5-yl)piperidin-4-yl)((3R)-3-methoxypyrrolidin-1-yl)methanone

385.1 305 N-methyl-1-(4-(4-methyl-1H- pyrazol-1-yl)pyridin-3-yl)-N-((3S)-tetrahydrofuran-3- yl)piperidine-4-carboxamide

370.1

TABLE 1-32 EXAMPLE IUPACNAME Structure MS 306N-methyl-1-(4-(4-methyl-1H- pyrazol-1-yl)pyridin-3-yl)-N-((3R)-tetrahydrofuran-3- yl)piperidine-4-carboxamide

370.1 307 1-(4-(4-chloro-1H-pyrazol-1- yl)pyridin-3-yl)-N-methyl-N-((3S)-tetrahydrofuran-3- yl)piperidine-4-carboxamide

390.1 308 1-(4-(4-chloro-1H-pyrazol-1- yl)pyridin-3-yl)-N-methyl-N-((3R)-tetrahydrofuran-3- yl)piperidine-4-carboxamide

390.1 309 1-(4-(4-fluorophenyl)pyrimidin- 5-yl)-N-methyl-N-((3S)-tetrahydrofuran-3-yl)piperidine- 4-carboxamide

385.1 310 1-(4-(4-fluoropbenyl)pyrimidin- 5-yl)-N-methyl-N-((3R)-tetrahydrofuran-3-yl)piperidine- 4-carboxamide

385.1 311 N-(2-fluoroethyl)-1-(4-(4- methyl-1H-pyrazol-1-yl)pyridin-3-yl)-N-(tetrahydro-2H-pyran-4- yl)piperidine-4-carboxamide

416.2 312 N-(2-fluoroethyl)-1-(4-(4- methyl-1H-pyrazol-1-yl)pyridin-3-yl)-N-((3S)-tetrahydrofuran-3- yl)piperidine-4-carboxamide

402.1 313 N-(2-fluoroethyl)-1-(4-(4- methyl-1H-pyrazol-1-yl)pyridin-3-yl)-N-((3R)-tetrahydrofuran-3- yl)piperidine-4-carboxamide

402.1

TABLE 1-33 EXAMPLE IUPACNAME Structure MS 314N-benzyl-N-(2-fluoroethyl)-4-(4- phenylpyrimidin-5-yl)piperazine-1-carboxamide

420.0 315 N-(4-fluorobenzyl)-N-(2- fluoroethyl)-4-(4-(4-methyl-1H-pyrazol-1-yl)pyridin-3- yl)piperazine-1-carboxamide

441.1 316 ((3S)-3-fluoropyrrolidin-1- yl)(1-(4-(5-methyl-1,3-thiazol-2-yl)pyridin-3-yl)piperidin-4- yl)methanone

375.0 317 (3-fluoroazetidin-1-yl)(1-(4-(5-methyl-1,3-thiazol-2-yl)pyridin- 3-yl)piperidin-4-yl)methanone

361.1 318 (1-(4-(4-bromo-1H-pyrazol-1- yl)pyridin-3-yl)piperidin-4-yl)((3S)-3-fluoropyrrolidin-1- yl)methanone

421.9 319 (1-(4-(4-bromo-1H-pyrazol-1- yl)pyridin-3-yl)piperidin-4-yl)(3-fluoroazetidin-1- yl)methanone

408.0 320 N,N-diethyl-1-(4-(4-methyl-1H- pyrazol-1-yl)pyridin-3-yl)piperidine-4-carboxamide

342.1 321 N-ethyl-N-methyl-1-(4-(4- methyl- 1H-pyrazol-1-yl)pyridin-3-yl)piperidine-4-carboxamide

328.2 322 (1-(4-(4-cyclopropyl-1H- pyrazol-1-yl)pyridin-3-yl)piperidin-4- yl)((3S)-3-fluoropyrrolidin- 1-yl)methanone

384.0 323 (1-(4-(4-cyclopropyl-1H- pyrazol-1-yl)pyridin-3-yl)piperidin-4- yl)(3-fluoroazetidin-1- yl)methanone

370.0

Formulation Example 1 (Production of Capsule)

1) compound of Example 1 30 mg 2) fine powder cellulose 10 mg 3) lactose19 mg 4) magnesium stearate  1 mg Total 60 mg

1), 2), 3) and 4) are mixed and filled in a gelatin capsule.

Formulation Example 2 (Production of Tablet)

1) compound of Example 1  30 g 2) lactose  50 g 3) cornstarch  15 g 4)calcium carboxymethylcellulose  44 g 5) magnesium stearate  1 g 1000tablets total 140 g

The total amount of 1), 2) and 3) and 4) (30 g) is kneaded with water,vacuum dried, and sieved. The sieved powder is mixed with 4) (14 g) and5) (1 g), and the mixture is punched by a tableting machine, whereby1000 tablets containing 30 mg of the compound of Example 1 per tabletare obtained.

Experimental Example 1: Construction of Human CH24H (CYP46) ExpressionVector

A plasmid DNA for expressing human CH24H in a FreeStyle 293 cell wasproduced as follows. Using Full-Length Mammalian Gene Collection No.4819975 (Invitrogen) as a template, and the following two kinds ofsynthesized DNAs:

(SEQ ID NO: 1) 5′-GCCCCGGAGCCATGAGCCCCGGGCTG-3′ and (SEQ ID NO: 2)5′-GTCCTGCCTGGAGGCCCCCTCAGCAG-3′,PCR was performed to amplify 91-1625 bp region of human CH24H(BC022539). The obtained fragment was cloned using TOPO TA Cloning Kit(Invitrogen). The obtained fragment was subcloned to pcDNA3.1(+)digested with BamHI and XhoI to give a plasmid DNA for human CH24Hexpression (pcDNA3.1(+)/hCH24H).

Experimental Example 2: Expression of Human CH24H and Preparation ofHuman CH24H Lysate

The expression of human CH24H was performed using FreeStyle 293Expression System (Invitrogen). According to the manual attached toFreeStyle 293 Expression System and using the plasmid DNA for humanCH24H expression (pcDNA3.1(+)/hCH24H) constructed in ExperimentalExample 1, a transient expression using FreeStyle 293-F cell wasperformed. After transfection, the cells were cultured at 37° C., 8% CO₂with shaking at 125 rpm for 2 days. The cells were collected bycentrifugation, and suspended in a suspension buffer (100 mM potassiumphosphate (pH 7.4), 0.1 mM EDTA, 1 mM DTT, 20% Glycerol). The suspendedproduct was disrupted by a polytron homogenizer (manufactured byKinematica), and centrifuged at 9000×g for 10 min, and the supernatantwas collected. The collected supernatant was cryopreserved (−80° C.) asa human CH24H lysate standard product.

Experimental Example 3: Measurement of CH24H Inhibitory Activity

For the measurement of CH24H inhibitory activity, using the human CH24Hlysate prepared in Experimental Example 2, the amount of 24-HC producedfrom cholesterol by catalytic activity of CH24H was measured in thepresence of a test compound, and compared with that measured in theabsence of the test compound. That is, a test compound solution atvarious concentrations was mixed with a reaction buffer (50 mM potassiumphosphate containing 0.1% BSA and Complete, EDTA-free, pH 7.4) and humanCH24H lysate. Then, [¹⁴C] cholesterol (53 mCi/mmol specific activity, 15μM) was added, and CH24H reaction was performed at 37° C. for 5 hr.After completion of the reaction, a quenching solution consisting ofchloroform/methanol/distilled water (2:2:1 v/v) was added, and theresulting 24-HC was extracted by shaking. The extract was applied tosilica gel thin layer chromatography (ethyl acetate:toluene=4:6), andthe obtained ¹⁴C-24HC fraction was measured with BAS2500 (FujifilmCorporation).

The inhibitory rate (%) was calculated from the ratio of radioactivityin the presence of a test compound relative to the radioactivity in theabsence of the test compound. The results are shown in the followingTable 2.

TABLE 2 Test Inhibitory Rate Compound in 1 μM (%) Example 1 90 Example 280 Example 12 90 Example 13 89 Example 21 85 Example 24 96 Example 25 97Example 26 98 Example 29 97 Example 30 97 Example 31 97 Example 33 96Example 35 98 Example 38 98 Example 43 98 Example 59 92 Example 70 97Example 73 97 Example 79 93 Example 82 97 Example 83 74 Example 87 98Example 114 86 Example 117 85 Example 119 93 Example 120 95 Example 12180 Example 124 81 Example 127 79 Example 128 97 Example 129 82 Example130 93 Example 131 87 Example 132 87 Example 133 87 Example 138 93Example 142 93 Example 143 98 Example 144 98 Example 148 92 Example 15290 Example 153 85 Example 158 85 Example 161 56 Example 165 86 Example169 97 Example 170 86 Example 172 96 Example 175 95 Example 176 82Example 177 92 Example 180 87 Example 183 92 Example 188 81 Example 19087 Example 193 90 Example 194 93 Example 198 90 Example 200 88 Example213 93 Example 214 89 Example 222 92 Example 54 99 Example 58 96 Example86 98 Example 277 94 Example 278 75 Example 280 78 Example 281 84Example 282 83 Example 283 85 Example 284 80 Example 285 82 Example 28683 Example 287 89 Example 288 84 Example 296 86 Example 297 84 Example298 79 Example 299 84 Example 300 83 Example 301 86 Example 302 87Example 303 85 Example 304 86 Example 305 85 Example 306 85 Example 30781 Example 308 83 Example 309 85 Example 310 82 Example 311 79 Example312 71 Example 313 82 Example 314 91 Example 315 94 Example 316 94Example 317 95 Example 318 94 Example 319 96 Example 322 93 Example 32393

Experimental Example 4: Quantification Test of 24-HC

Animals used were 6-week-old female C57BL/6N mice (3 mice/group). A testcompound was suspended in a 0.5% aqueous methylcellulose [133-14255WAKO] solution (1 mg/mL). The body weight of the mice was measured, andthe solution was forcibly administered orally and repeatedly once a dayfor 3 days. At 16 hours after the third administration, half of thebrain was harvested, and the amount of 24-HC was measured.

The wet weight of the brain was measured, and the brain was homogenizedwith 4-fold amount of saline. This solution was used as a brain extract.The 24-HC in the brain extract was extracted with an acetonitrilesolution (98% acetonitrile, 1.98% methanol, 0.02% formic acid), andquantified by HPLC. The average value of 24-HC amount was calculated andthe results are shown in relative values with the control group as 100%.The results are shown in the following Table 3.

TABLE 3 Test Decreasing Rate Compound in 30 mg/kg (%) Example 33 49Example 70 61 Example 124 59 Example 127 44 Example 129 44 Example 13054 Example 132 65 Example 133 70 Example 142 69

Experimental Example 5: Novel Object Recognition Test Using an APPTransgenic Mouse (Tg2576)

Animals used were 6-week-old Tg2576 mice and their wild-type mice (10mice/group). A test compound was suspended in a 0.5% aqueous methylcellulose [133-14255 WAKO] solution (3 mg/mL). The body weight of themice was measured, and the solution was forcibly administered orally andrepeatedly at 10 mL/kg once a day for 6 weeks. Then, a novel objectrecognition test was performed as follows. On the day before acquisitiontrial, the mice kept in the same cage were put in an observation box inwhich the illuminance was set to 300 lx, and habituated for 30 min.After the habituation, a compound was orally administered. On the nextday, the mice were put, as an acquisition trial, in an observation boxin which two same objects were placed, and the number and duration ofcontacts to the objects were measured for 5 min under 300 lx. A compoundwas orally administered after the measurement. The day after theacquisition trial, the one object was replaced with a novel object, andthe number and duration of contacts to each of the object were measuredfor 5 min. A metal cylinder and ceramic triangular pyramid were used inthis test. A control group (test compound-untreated group) and a controlgroup in wild-type mice were used for comparison. The results are shownas the rate (%) of the number and duration of contacts to the novelobject relative to the total number and duration of contacts to theobjects. The results are shown in the following Table 4.

TABLE 4 wild-type mice APP transgenic mouse control group control groupExample 70 exploration number of 61.2 50.0 55.2 Rate (%) of contactsNovel Object duration of 69.7 52.1 65.2 contacts

INDUSTRIAL APPLICABILITY

The compound of the present invention has a superior CH24H inhibitoryaction, which is useful as an agent for the prophylaxis or treatment ofepilepsy, neurodegenerative disease (e.g., Alzheimer's disease, mildcognitive disorder, Huntington's disease, Parkinson's disease, multiplesclerosis, amyotrophic lateral sclerosis, traumatic brain injury,cerebral infarction, glaucoma and the like), schizophrenia and the like.

This application is based on patent applications No. 2012-270445 filedon Dec. 11, 2012 and No. 2013-210439 filed on Oct. 7, 2013 in Japan, thecontents of which are encompassed in full herein.

1. A compound represented by the formula (I):

wherein X¹ is a carbon atom or a nitrogen atom; Ring A is

each of which is optionally further substituted and optionally bridged;R¹ is an optionally substituted C₁₋₆ alkyl group, an optionallysubstituted hydroxy group, an optionally substituted amino group, anoptionally substituted carbocyclic group, or an optionally substitutedheterocyclic group, or R¹ is optionally bonded to the atom on Ring A toform, together with Ring A, a spiro ring or a fused ring, each of whichis substituted by an oxo group and optionally further substituted; R² isan optionally substituted C₆₋₁₄ aryl group, or an optionally substitutedaromatic heterocyclic group; and R³ is a hydrogen atom or a substituentwhen X¹ is a carbon atom, or absent when X¹ is a nitrogen atom,(tert-butyl 4-(4-phenylpyrimidin-5-yl)piperazine-1-carboxylate isexcluded) or a salt thereof.
 2. The compound or salt of claim 1, whereinR¹ is an optionally substituted C₁₋₆ alkyl group, an optionallysubstituted C₁₋₆ alkoxy group, an optionally substituted amino group, anoptionally substituted C₃₋₈ cycloalkyl group, an optionally substitutedC₆₋₁₄ aryl group, or an optionally substituted non-aromatic heterocyclicgroup (tert-butyl 4-(4-phenylpyrimidin-5-yl)piperazine-1-carboxylate isexcluded).
 3. The compound or salt of claim 1, wherein R¹ is (1) a C₁₋₆alkyl group optionally substituted by 1 to 3 substituents selected from(a) a cyano group, (b) a C₆₋₁₄ aryl group optionally substituted by 1 to3 C₁₋₆ alkoxy groups, (c) a C₆₋₁₄ aryloxy group, (d) a C₃₋₈ cycloalkylgroup, (e) a pyrazolyl group, (f) an indazolyl group, and (g) adihydropyridyl group optionally substituted by 1 to 3 oxo groups, (2) aC₁₋₆ alkoxy group optionally substituted by 1 to 3 C₆₋₁₄ aryl groups,(3) an amino group optionally mono- or di-substituted by substituent(s)selected from (a) a C₁₋₆ alkyl group optionally substituted by 1 to 3substituents selected from (i) a halogen atom, (ii) a cyano group, (iii)a C₃₋₈ cycloalkyl group, (iv) a C₆₋₁₄ aryl group optionally substitutedby 1 to 3 substituents selected from a halogen atom and a C₁₋₆ alkoxygroup, (v) a pyridyl group, and (vi) an oxetanyl group optionallysubstituted by 1 to 3 C₁₋₆ alkyl groups, (b) a C₃₋₈ cycloalkyl groupoptionally substituted by 1 to 3 halogen atoms, (c) a C₆₋₁₄ aryl group,and (d) a tetrahydropyranyl group, an oxetanyl group, a tetrahydrofurylgroup and a pyrrolidinyl group, each of which is optionally substitutedby 1 to 3 C₁₋₆ alkyl groups, (4) a C₃₋₈ cycloalkyl group optionallysubstituted by 1 to 3 C₆₋₁₄ aryl groups, (5) a C₆₋₁₄ aryl group, or (6)a 3- to 8-membered monocyclic non-aromatic heterocyclic group or a3,7-dioxa-9-azabicyclo[3.3.1]nonyl group, each of which is optionallysubstituted by 1 to 5 substituents selected from (a) a halogen atom, (b)a cyano group, (c) a hydroxy group, (d) an oxo group, (e) a carbamoylgroup optionally mono- or di-substituted by C₁₋₆ alkyl group(s), (f) aC₁₋₆ alkyl group optionally substituted by 1 to 3 substituents selectedfrom (i) a hydroxy group, and (ii) a C₁₋₆ alkoxy group, (g) a C₁₋₆alkoxy group optionally substituted by 1 to 3 halogen atoms, (h) a C₁₋₆alkoxy-carbonyl group, and (i) a C₆₋₁₄ aryl group optionally substitutedby 1 to 3 halogen atoms, or R¹ is bonded to the atom on Ring A to form,together with Ring A, a 2,8-diazaspiro[4.5]decane ring substituted byoxo and optionally further substituted by 1 to 3 C₁₋₆ alkyl groups; R²is (1) a C₆₋₁₄ aryl group optionally substituted by 1 to 3 substituentsselected from (a) a halogen atom, and (b) a C₁₋₆ alkyl group optionallysubstituted by 1 to 3 halogen atoms, or (2) a 5- or 6-memberedmonocyclic aromatic heterocyclic group or a 8- to 12-membered fusedaromatic heterocyclic group, each of which is optionally substituted by1 to 3 substituents selected from (a) a halogen atom, (b) a cyano group,(c) a C₁₋₆ alkyl group optionally substituted by 1 to 3 halogen atoms,and (d) a C₃₋₈ cycloalkyl group; X¹ is a carbon atom or a nitrogen atom;R³ is (1) a hydrogen atom, or (2) a halogen atom; and Ring A is (1)

each of which is optionally further substituted by 1 to 3 substituentsselected from (a) a halogen atom, (b) a C₁₋₆ alkyl group, and (c) an oxogroup, or (2) a 8-azabicyclo[3.2.1]octane ring, a2,5-diazabicyclo[2.2.1]heptane ring or a 3-azabicyclo[3.1.0]hexane ring,(tert-butyl 4-(4-phenylpyrimidin-5-yl)piperazine-1-carboxylate isexcluded).
 4. The compound or salt of claim 3, wherein R¹ is (1) a C₁₋₆alkyl group optionally substituted by 1 to 3 substituents selected from(a) a cyano group, (b) a C₆₋₁₄ aryl group optionally substituted by 1 to3 C₁₋₆ alkoxy groups, (c) a C₆₋₁₄ aryloxy group, (d) a C₃₋₈ cycloalkylgroup, (e) a pyrazolyl group, (f) an indazolyl group, and (g) adihydropyridyl group optionally substituted by 1 to 3 oxo groups, (2) aC₁₋₃ alkoxy group optionally substituted by 1 to 3 C₆₋₁₄ aryl groups,(3) an amino group optionally mono- or di-substituted by substituent(s)selected from (a) a C₁₋₆ alkyl group optionally substituted by 1 to 3substituents selected from (i) a halogen atom, (ii) a cyano group, (iii)a C₃₋₈ cycloalkyl group, (iv) a C₆₋₁₄ aryl group optionally substitutedby 1 to 3 substituents selected from a halogen atom and a C₁₋₆ alkoxygroup, (v) a pyridyl group, and (vi) an oxetanyl group optionallysubstituted by 1 to 3 C₁₋₆ alkyl groups, (b) a C₃₋₈ cycloalkyl groupoptionally substituted by 1 to 3 halogen atoms, (c) a C₆₋₁₄ aryl group,and (d) a tetrahydropyranyl group, an oxetanyl group, a tetrahydrofurylgroup and a pyrrolidinyl group, each of which is optionally substitutedby 1 to 3 C₁₋₆ alkyl groups, (4) a C₃₋₈ cycloalkyl group optionallysubstituted by 1 to 3 C₆₋₁₄ aryl groups, (5) a C₆₋₁₄ aryl group, or (6)a 3- to 8-membered monocyclic non-aromatic heterocyclic group or a3,7-dioxa-9-azabicyclo[3.3.1]nonyl group, each of which is optionallysubstituted by 1 to 5 substituents selected from (a) a halogen atom, (b)a cyano group, (c) a hydroxy group, (d) an oxo group, (e) a carbamoylgroup optionally mono- or di-substituted by C₁₋₆ alkyl group(s), (f) aC₁₋₆ alkyl group optionally substituted by 1 to 3 substituents selectedfrom (i) a hydroxy group, and (ii) a C₁₋₆ alkoxy group, (g) a C₁₋₆alkoxy group optionally substituted by 1 to 3 halogen atoms, (h) a C₁₋₆alkoxy-carbonyl group, and (i) a C₆₋₁₄ aryl group optionally substitutedby 1 to 3 halogen atoms, or R¹ is bonded to the atom on Ring A to form,together with Ring A, a 2,8-diazaspiro[4.5]decane ring substituted byoxo and optionally further substituted by 1 to 3 C₁₋₆ alkyl groups. 5.The compound or salt of claim 1, wherein R¹ is (1) an amino groupoptionally mono- or di-substituted by substituent(s) selected from (a) aC₁₋₆ alkyl group optionally substituted by 1 to 3 substituents selectedfrom (i) a halogen atom, and (ii) a phenyl group optionally substitutedby 1 to 3 halogen atoms, (b) a tetrahydropyranyl group, and (c) atetrahydrofuryl group, or (2) an azetidinyl group or a pyrrolidinylgroup, each of which is optionally substituted by 1 to 5 substituentsselected from (a) a halogen atom, (b) a cyano group, (c) a carbamoylgroup, (d) a C₁₋₆ alkyl group, and (e) a C₁₋₆ alkoxy group; R² is (1) aphenyl group optionally substituted by 1 to 3 halogen atoms, or (2) apyrazolyl group, a thiazolyl group or a thiadiazolyl group, each ofwhich is optionally substituted by 1 to 3 substituents selected from (a)a halogen atom, (b) a C₁₋₆ alkyl group, and (c) a cyclopropyl group; X¹is a carbon atom or a nitrogen atom; R¹ is a hydrogen atom; and Ring Ais


6. The compound or salt of claim 1, wherein R¹ is a pyrrolidinyl groupoptionally substituted by 1 to 5 substituents selected from (a) ahalogen atom, and (b) a cyano group; R² is a pyrazolyl group optionallysubstituted by 1 to 3 substituents selected from (a) a halogen atom, and(b) a C₁₋₆ alkyl group; X¹ is a carbon atom; R³ is a hydrogen atom; andRing A is

7.(3-fluoroazetidin-1-yl)(1-(4-(4-fluorophenyl)pyrimidin-5-yl)piperidin-4-yl)methanoneor a salt thereof,(1-(4-(4-chloro-1H-pyrazol-1-yl)pyridin-3-yl)piperidin-4-yl)(3-fluoroazetidin-1-yl)methanoneor a salt thereof,(1-(4-(4-chloro-1H-pyrazol-1-yl)pyridin-3-yl)piperidin-4-yl)((3S)-3-fluoropyrrolidin-1-yl)methanoneor a salt thereof,(1-(4-(4-fluorophenyl)pyrimidin-5-yl)piperidin-4-yl)((3S)-3-fluoropyrrolidin-1-yl)methanoneor a salt thereof,N-benzyl-N-(2-fluoroethyl)-4-(4-phenylpyrimidin-5-yl)piperazine-1-carboxamideor a salt thereof,N-(4-fluorobenzyl)-N-(2-fluoroethyl)-4-(4-(4-methyl-1H-pyrazol-1-yl)pyridin-3-yl)piperazine-1-carboxamideor a salt thereof,((3S)-3-fluoropyrrolidin-1-yl)(1-(4-(5-methyl-1,3-thiazol-2-yl)pyridin-3-yl)piperidin-4-yl)methanoneor a salt thereof,(3-fluoroazetidin-1-yl)(1-(4-(5-methyl-1,3-thiazol-2-yl)pyridin-3-yl)piperidin-4-yl)methanoneor a salt thereof,(1-(4-(4-bromo-1H-pyrazol-1-yl)pyridin-3-yl)piperidin-4-yl)(3-fluoroazetidin-1-yl)methanoneor a salt thereof, or(1-(4-(4-cyclopropyl-1H-pyrazol-1-yl)pyridin-3-yl)piperidin-4-yl)(3-fluoroazetidin-1-yl)methanoneor a salt thereof. 8-10. (canceled)
 11. A medicament comprising thecompound or salt of claim
 1. 12-17. (canceled)
 18. A method for theprophylaxis or treatment of epilepsy or neurodegenerative disease, whichcomprises administering an effective amount of the compound or salt ofclaim 1 to the mammal.
 19. The method of claim 18, wherein theneurodegenerative disease is Alzheimer's disease, mild cognitivedisorder, Huntington's disease, Parkinson's disease or multiplesclerosis. 20-21. (canceled)